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Kumar Maji R, Fischer A, Rogg EM, Möller M, Gasparoni G, Simon M, Dimmeler S, Schulz MH. A cell type-specific expression atlas of small and total RNA in the heart after myocardial infarction. Sci Data 2025; 12:816. [PMID: 40389446 PMCID: PMC12089340 DOI: 10.1038/s41597-025-05061-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2024] [Accepted: 04/24/2025] [Indexed: 05/21/2025] Open
Abstract
Acute myocardial infarction (AMI) is a leading cause of mortality worldwide. MicroRNAs (miRNAs), among other small non-coding RNAs, shape the transcriptome and control cellular functions. Although single-cell technologies are now available to study myocardial ischemia response, the study of small RNA regulation is limited by depth of expression, capture efficiency and lack of full coverage of transcripts. In addition, the kinetic expression of miRNAs is unknown. Using paired small and total RNA sequencing, we built an expression atlas to study the temporal dynamics of miRNAs and genes in four major heart cell types after AMI. Expression dynamics reveal enriched functions highlighting cell type-specific AMI stress responses. Many deregulated mouse genes after AMI overlap with known human cardiovascular disease genes. The dataset is highly valuable for additional research on small and long non-coding RNAs, such as regulation of RNA variants by splicing or alternative ORFs. All in all, the RNA expression atlas provides a useful resource to study different roles of RNAs in major cell types of the heart after AMI.
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Affiliation(s)
- Ranjan Kumar Maji
- Institute for Cardiovascular Regeneration, Goethe-University; German Centre for Cardiovascular Research (DZHK), Partner site Rhine-Main, 60590, Frankfurt, Germany
- Institute for Computational Genomic Medicine, Goethe University Frankfurt, 60590, Frankfurt, Germany
| | - Ariane Fischer
- Institute for Cardiovascular Regeneration, Goethe-University; German Centre for Cardiovascular Research (DZHK), Partner site Rhine-Main, 60590, Frankfurt, Germany
| | - Eva-Maria Rogg
- Institute for Cardiovascular Regeneration, Goethe-University; German Centre for Cardiovascular Research (DZHK), Partner site Rhine-Main, 60590, Frankfurt, Germany
- Immundiagnostik AG, 64625, Bensheim, Germany
| | - Melanie Möller
- Molecular Cell Biology & Microbiology, Wuppertal University, Wuppertal, Germany
| | | | - Martin Simon
- Molecular Cell Biology & Microbiology, Wuppertal University, Wuppertal, Germany
| | - Stefanie Dimmeler
- Institute for Cardiovascular Regeneration, Goethe-University; German Centre for Cardiovascular Research (DZHK), Partner site Rhine-Main, 60590, Frankfurt, Germany.
| | - Marcel H Schulz
- Institute for Cardiovascular Regeneration, Goethe-University; German Centre for Cardiovascular Research (DZHK), Partner site Rhine-Main, 60590, Frankfurt, Germany.
- Institute for Computational Genomic Medicine, Goethe University Frankfurt, 60590, Frankfurt, Germany.
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Ghosh S, Mandal S, Das A, Shukla PC, Das S. Probing Shear-Induced Endothelial Activation in Vascular Conditions Using On-Chip Models. ACS Biomater Sci Eng 2025; 11:2677-2689. [PMID: 40214744 DOI: 10.1021/acsbiomaterials.4c02164] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/13/2025]
Abstract
Hemodynamic fluctuations at vessel bifurcation impact the development of atherosclerosis and aneurysms. A novel glass capillary tube-based lithography-free technique was used for fabricating vessel bifurcations with stenosis and aneurysm at the junction of bifurcation to determine the endothelial response to arterial shear rates in vitro. At variable shear rates of 1-2000 s-1, representative of conditions in the aorta, the endothelial cell responses under flow disturbances encountered in stenosed and aneurysmal vessels were modeled. Mechanical disturbances induce greater endothelial activation at stenosis, while increased VE-cadherin expression deters activation at dilations. The endothelial responses to disturbed flow were better observed at the area of bifurcation, where the increase in shear forces and reduced pressure marginally compensated for cellular activation. The comparative model was established using an image analysis approach for the assessment of endothelial responses toward disease progression at bifurcations. No significant differences in endothelial markers were observed under inflammatory stress and physiologically relevant mechanical stresses due to compensatory effects of inflammatory cytokines inducing NF-κβ activation, as seen using this frugal approach.
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Affiliation(s)
- Swachhatoa Ghosh
- School of Medical Science and Technology, IIT Kharagpur, Kharagpur 721302, India
| | - Shreya Mandal
- Department of Bioscience and Biotechnology, IIT Kharagpur, Kharagpur 721302, India
| | - Abhijit Das
- Department of Bioscience and Biotechnology, IIT Kharagpur, Kharagpur 721302, India
| | - Praphulla C Shukla
- School of Medical Science and Technology, IIT Kharagpur, Kharagpur 721302, India
| | - Soumen Das
- School of Medical Science and Technology, IIT Kharagpur, Kharagpur 721302, India
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3
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Meecham A, McCurdy S, Frias-Anaya E, Li W, Gallego-Gutierrez H, Nguyen P, Li YS, Chien S, Shyy JYJ, Ginsberg MH, Lopez-Ramirez MA. Silencing KRIT1 Partially Reverses the Effects of Disturbed Flow on the Endothelial Cell Transcriptome. Int J Mol Sci 2025; 26:4340. [PMID: 40362576 PMCID: PMC12072803 DOI: 10.3390/ijms26094340] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2025] [Revised: 04/19/2025] [Accepted: 04/29/2025] [Indexed: 05/15/2025] Open
Abstract
Endothelial cells respond to forces generated by laminar blood flow with changes in vasodilation, anticoagulant, fibrinolytic, or anti-inflammatory functions which preserve vessel patency. These responses to flow shear stress are primarily mediated by the modulation of the following transcription factors: Krüppel-like factors 2 and 4 (KLF2 and KLF4). Notably, disturbed flow patterns, which are found in vascular areas predisposed to atherosclerosis, significantly reduce the endothelial expression of KLF2 and KLF4, resulting in changes in the transcriptome that exacerbate inflammation and thrombosis. The endothelial CCM (Cerebral Cavernous Malformation) complex, comprising KRIT1 (Krev1 interaction trapped gene 1), CCM2 (Malcavernin), and CCM3 (Programmed cell death protein 10), suppresses the expression of KLF2 and KLF4. Loss of function of the CCM complex has recently been suggested to protect from coronary atherosclerosis in humans. We thus hypothesized that the silencing of KRIT1, the central scaffold of the CCM complex, can normalize the atherogenic effects of disturbed flow on the human endothelial transcriptome. Bulk RNA sequencing (RNA-seq) was conducted on human umbilical vein endothelial cells (HUVECs) after the expression of KRIT1 was silenced using specific small interfering RNA (siRNA). The endothelial cells were exposed to three different conditions for 24 h, as follows: pulsatile shear stress (laminar flow), oscillatory shear stress (disturbed flow), and static conditions (no flow). We found that silencing the KRIT1 expression in HUVECs restored the expression of the transcription factors KLF2 and KLF4 under oscillatory shear stress. This treatment resulted in a transcriptomic profile similar to that of endothelial cells under pulsatile shear stress. These findings suggest that inhibition of the CCM complex in endothelium plays a vasoprotective role by reactivating a protective gene program to help endothelial cells resist disturbed blood flow. Targeting CCM genes can activate well-known vasoprotective gene programs that enhance endothelial resilience to inflammation, hypoxia, and angiogenesis under disturbed flow conditions, providing a novel pathway for preventing atherothrombosis.
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Affiliation(s)
- Amelia Meecham
- Department of Medicine, University of California, La Jolla, CA 92093, USA; (A.M.); (S.M.); (E.F.-A.); (W.L.); (H.G.-G.)
| | - Sara McCurdy
- Department of Medicine, University of California, La Jolla, CA 92093, USA; (A.M.); (S.M.); (E.F.-A.); (W.L.); (H.G.-G.)
| | - Eduardo Frias-Anaya
- Department of Medicine, University of California, La Jolla, CA 92093, USA; (A.M.); (S.M.); (E.F.-A.); (W.L.); (H.G.-G.)
| | - Wenqing Li
- Department of Medicine, University of California, La Jolla, CA 92093, USA; (A.M.); (S.M.); (E.F.-A.); (W.L.); (H.G.-G.)
| | - Helios Gallego-Gutierrez
- Department of Medicine, University of California, La Jolla, CA 92093, USA; (A.M.); (S.M.); (E.F.-A.); (W.L.); (H.G.-G.)
| | - Phu Nguyen
- Department of Bioengineering, University of California, La Jolla, CA 92093, USA; (P.N.); (Y.-S.L.); (S.C.); (J.Y.-J.S.)
| | - Yi-Shuan Li
- Department of Bioengineering, University of California, La Jolla, CA 92093, USA; (P.N.); (Y.-S.L.); (S.C.); (J.Y.-J.S.)
| | - Shu Chien
- Department of Bioengineering, University of California, La Jolla, CA 92093, USA; (P.N.); (Y.-S.L.); (S.C.); (J.Y.-J.S.)
| | - John Y.-J. Shyy
- Department of Bioengineering, University of California, La Jolla, CA 92093, USA; (P.N.); (Y.-S.L.); (S.C.); (J.Y.-J.S.)
| | - Mark H. Ginsberg
- Department of Medicine, University of California, La Jolla, CA 92093, USA; (A.M.); (S.M.); (E.F.-A.); (W.L.); (H.G.-G.)
| | - Miguel Alejandro Lopez-Ramirez
- Department of Medicine, University of California, La Jolla, CA 92093, USA; (A.M.); (S.M.); (E.F.-A.); (W.L.); (H.G.-G.)
- Department of Pharmacology, University of California, La Jolla, CA 92093, USA
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Batta SPR, Rio M, Lebot C, Baron-Menguy C, Bodet M, Moutaoukil R, Le Ruz R, Babahnini I, Loirand G, Vion AC. ARHGEF18 is a flow-responsive exchange factor controlling endothelial tight junctions and vascular leakage. Cell Rep 2025; 44:115288. [PMID: 39977269 DOI: 10.1016/j.celrep.2025.115288] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2023] [Revised: 11/20/2024] [Accepted: 01/17/2025] [Indexed: 02/22/2025] Open
Abstract
The shear stress resulting from blood flow is a major regulator of endothelial cell (EC) biology and morphology. Rho protein-mediated cytoskeleton remodeling is an early and essential step of EC responses to flow. However, how Rho protein signaling is controlled by shear stress remains unclear. Here we demonstrate that phosphorylation, activity, and expression of the Rho nucleotide exchange factor (RhoGEF) ARHGEF18 in ECs are modulated by the magnitude of shear stress. When phosphorylated, ARHGEF18 interacts with tight junctions; participates in EC elongation, alignment, and migration; and allows the maintenance of the endothelial barrier under physiological flow conditions. In mice, ARHGEF18 is involved in tight junction formation, flow response of ECs, and the control of vascular permeability. Together, our results identified ARHGEF18 as the first flow-sensitive RhoGEF in ECs, whose activity is essential for the maintenance of intercellular junctions and the control of vascular permeability in vivo.
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Affiliation(s)
| | - Marc Rio
- Université de Nantes, CHU Nantes, CNRS, INSERM, l'institut du thorax, 44000 Nantes, France
| | - Corentin Lebot
- Université de Nantes, CHU Nantes, CNRS, INSERM, l'institut du thorax, 44000 Nantes, France
| | - Céline Baron-Menguy
- Université de Nantes, CHU Nantes, CNRS, INSERM, l'institut du thorax, 44000 Nantes, France
| | - Maxence Bodet
- Université de Nantes, CHU Nantes, CNRS, INSERM, l'institut du thorax, 44000 Nantes, France
| | - Reda Moutaoukil
- Université de Nantes, CHU Nantes, CNRS, INSERM, l'institut du thorax, 44000 Nantes, France
| | - Robin Le Ruz
- Université de Nantes, CHU Nantes, CNRS, INSERM, l'institut du thorax, 44000 Nantes, France
| | - Ibtissam Babahnini
- Université de Nantes, CHU Nantes, CNRS, INSERM, l'institut du thorax, 44000 Nantes, France
| | - Gervaise Loirand
- Université de Nantes, CHU Nantes, CNRS, INSERM, l'institut du thorax, 44000 Nantes, France.
| | - Anne-Clémence Vion
- Université de Nantes, CHU Nantes, CNRS, INSERM, l'institut du thorax, 44000 Nantes, France.
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5
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Meecham A, McCurdy S, Frias-Anaya E, Li W, Gallego-Gutierrez H, Ngyuen P, Li JYS, Chien S, Shyy JYJ, Ginsberg MH, Lopez-Ramirez MA. Silencing KRIT1 Partially Reverses the Effects of Disturbed Flow on the Endothelial Cell Transcriptome. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.03.12.642862. [PMID: 40161739 PMCID: PMC11952409 DOI: 10.1101/2025.03.12.642862] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 04/02/2025]
Abstract
Background Endothelial cells respond to forces generated by laminar blood flow with changes in vasodilation, anticoagulant, fibrinolytic, or anti-inflammatory functions which preserve vessel patency. These responses to flow sheer stress are primarily mediated by the modulation of transcription factors Krüppel-like factors 2 and 4 (KLF2 and KLF4). Notably, disturbed flow patterns, which are found in vascular areas predisposed to atherosclerosis, significantly reduce the endothelial expression of KLF2 and KLF4, resulting in changes in the transcriptome that exacerbate inflammation and thrombosis. The endothelial CCM complex, comprising KRIT1, CCM2, and CCM3, suppresses the expression of KLF2 and KLF4. Loss of function of the CCM complex has recently been suggested to protect from coronary atherosclerosis in humans. We thus hypothesized that silencing of KRIT1, the central scaffold of the CCM complex, can normalize the atherogenic effects of disturbed flow on the human endothelial transcriptome. Methods Bulk RNA sequencing (RNA-seq) was conducted on human umbilical vein endothelial cells (HUVECs) after the expression of KRIT1 was silenced using specific siRNAs. The endothelial cells were exposed to three different conditions for 24 hours: pulsatile shear stress (laminar flow), oscillatory shear stress (disturbed flow), and static conditions (no flow). Results We found that silencing KRIT1 expression in HUVECs restored the expression of the transcription factors KLF2 and KLF4 under oscillatory shear stress. This treatment resulted in a transcriptomic profile similar to that of endothelial cells under pulsatile shear stress. These findings suggest that inhibition of the CCM complex in endothelium plays a vasoprotective role by reactivating a protective gene program to help endothelial cells resist disturbed blood flow. Conclusions Targeting CCM genes can activate well-known vasoprotective gene programs that enhance endothelial resilience to inflammation, hypoxia, and angiogenesis under disturbed flow conditions, providing a novel pathway for preventing atherosclerosis.
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Affiliation(s)
- Amelia Meecham
- Department of Medicine, University of California, San Diego, La Jolla, CA 92093
| | - Sara McCurdy
- Department of Medicine, University of California, San Diego, La Jolla, CA 92093
| | - Eduardo Frias-Anaya
- Department of Medicine, University of California, San Diego, La Jolla, CA 92093
| | - Wenqing Li
- Department of Medicine, University of California, San Diego, La Jolla, CA 92093
| | | | - Phu Ngyuen
- Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093
| | - Julie Yi-Shuan Li
- Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093
| | - Shu Chien
- Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093
| | - John Y.-J. Shyy
- Department of Medicine, University of California, San Diego, La Jolla, CA 92093
| | - Mark H. Ginsberg
- Department of Medicine, University of California, San Diego, La Jolla, CA 92093
| | - Miguel A. Lopez-Ramirez
- Department of Medicine, University of California, San Diego, La Jolla, CA 92093
- Department of Pharmacology, University of California, San Diego, La Jolla, CA 92093
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Oppenheim O, Giese W, Park H, Baumann E, Ivanov A, Beule D, Eichmann A, Gerhardt H. Divergent endothelial mechanisms drive arteriovenous malformations in Alk1 and SMAD4 loss-of-function. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.01.03.631070. [PMID: 39829872 PMCID: PMC11741317 DOI: 10.1101/2025.01.03.631070] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/22/2025]
Abstract
Hereditary hemorrhagic telangiectasia is an autosomal dominant disorder caused by mutations in the bone morphogenetic protein signaling pathway, leading to arteriovenous malformations. While previously thought to share molecular and cellular dysregulation, this study reveals highly distinct mechanisms depending on whether mutations occur in Alk1 or SMAD4. Loss of SMAD4 enhances endothelial cell responses to flow, including flow-regulated transcription and cell migration against blood flow, causing excessive pruning of capillaries and the formation of single large shunts. Conversely, Alk1 deficiency disrupts endothelial flow responses, including cell polarization and directional migration, leading to a dense vascular network and the persistence of a malformation nidus. In vivo cell population tracking of mutant cells validates unique endothelial cell migration defects. Mosaic cell culture models further illustrate that mutant cells co-opt wild-type cells driving distinct Alk1 or SMAD4 mutant-like behavioral defects. These findings demonstrate that arteriovenous malformations develop through fundamentally different cellular mechanisms based on the specific genetic mutation emphasizing the need for tailored diagnostic and therapeutic strategies.
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Affiliation(s)
- Olya Oppenheim
- Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany
- German Center for Cardiovascular Research (DZHK), Berlin, Germany
- Charité Universitätsmedizin Berlin, Germany
| | - Wolfgang Giese
- Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany
- German Center for Cardiovascular Research (DZHK), Berlin, Germany
| | - Hyojin Park
- Department of Molecular and Cellular Physiology, Yale University School of Medicine, New Haven, CT, USA
| | - Elisabeth Baumann
- Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany
- German Center for Cardiovascular Research (DZHK), Berlin, Germany
- Charité Universitätsmedizin Berlin, Germany
| | - Andranik Ivanov
- Charité Universitätsmedizin Berlin, Germany
- Berlin Institute of Health, Berlin, Germany
| | - Dieter Beule
- Charité Universitätsmedizin Berlin, Germany
- Berlin Institute of Health, Berlin, Germany
| | - Anne Eichmann
- Cardiovascular Research Center, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA
- Department of Molecular and Cellular Physiology, Yale University School of Medicine, New Haven, CT, USA
- PARCC, INSERM, Université de Paris, Paris, France
| | - Holger Gerhardt
- Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany
- German Center for Cardiovascular Research (DZHK), Berlin, Germany
- Charité Universitätsmedizin Berlin, Germany
- Berlin Institute of Health, Berlin, Germany
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Seetharaman S, Devany J, Kim HR, van Bodegraven E, Chmiel T, Tzu-Pin S, Chou WH, Fang Y, Gardel ML. Mechanosensitive FHL2 tunes endothelial function. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.06.16.599227. [PMID: 38948838 PMCID: PMC11212908 DOI: 10.1101/2024.06.16.599227] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/02/2024]
Abstract
Endothelial tissues are essential mechanosensors in the vasculature and facilitate adaptation to various blood flow-induced mechanical cues. Defects in endothelial mechanoresponses can perturb tissue remodelling and functions leading to cardiovascular disease progression. In this context, the precise mechanisms of endothelial mechanoresponses contributing to normal and diseased tissue functioning remain elusive. Here, we sought to uncover how flow-mediated transcriptional regulation drives endothelial mechanoresponses in healthy and atherosclerotic-prone tissues. Using bulk RNA sequencing, we identify novel mechanosensitive genes in response to healthy unidirectional flow (UF) and athero-prone disturbed flow (DF). We find that the transcription as well as protein expression of Four-and-a-half LIM protein 2 (FHL2) are enriched in athero-prone DF both in vitro and in vivo. We then demonstrate that the exogenous expression of FHL2 is necessary and sufficient to drive discontinuous adherens junction morphology and increased tissue permeability. This athero-prone phenotype requires the force-sensitive binding of FHL2 to actin. In turn, the force-dependent localisation of FHL2 to stress fibres promotes microtubule dynamics to release the RhoGEF, GEF-H1, and activate the Rho-ROCK pathway. Thus, we unravelled a novel mechanochemical feedback wherein force-dependent FHL2 localisation promotes hypercontractility. This misregulated mechanoresponse creates highly permeable tissues, depicting classic hallmarks of atherosclerosis progression. Overall, we highlight crucial functions for the FHL2 force-sensitivity in tuning multi-scale endothelial mechanoresponses.
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Affiliation(s)
- Shailaja Seetharaman
- Department of Physics, The University of Chicago, Chicago, IL 60637, USA
- James Franck Institute, The University of Chicago, Chicago, IL 60637, USA
- Institute for Biophysical Dynamics, The University of Chicago, Chicago, IL 60637, USA
| | - John Devany
- Department of Physics, The University of Chicago, Chicago, IL 60637, USA
- James Franck Institute, The University of Chicago, Chicago, IL 60637, USA
- Institute for Biophysical Dynamics, The University of Chicago, Chicago, IL 60637, USA
| | - Ha Ram Kim
- Pritzker School of Molecular Engineering, The University of Chicago, Chicago, IL 60637, USA
- Department of Medicine, Biological Sciences Division, The University of Chicago, Chicago, IL, 60637, USA
| | - Emma van Bodegraven
- Department of Translational Neuroscience, Brain Center, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
| | - Theresa Chmiel
- Department of Physics, The University of Chicago, Chicago, IL 60637, USA
- James Franck Institute, The University of Chicago, Chicago, IL 60637, USA
| | - Shentu Tzu-Pin
- Department of Medicine, Biological Sciences Division, The University of Chicago, Chicago, IL, 60637, USA
| | - Wen-hung Chou
- James Franck Institute, The University of Chicago, Chicago, IL 60637, USA
- Institute for Biophysical Dynamics, The University of Chicago, Chicago, IL 60637, USA
- Graduate Program in Biophysical Sciences, University of Chicago, Chicago, IL 60637, USA
| | - Yun Fang
- Department of Medicine, Biological Sciences Division, The University of Chicago, Chicago, IL, 60637, USA
| | - Margaret Lise Gardel
- Department of Physics, The University of Chicago, Chicago, IL 60637, USA
- James Franck Institute, The University of Chicago, Chicago, IL 60637, USA
- Institute for Biophysical Dynamics, The University of Chicago, Chicago, IL 60637, USA
- Pritzker School of Molecular Engineering, The University of Chicago, Chicago, IL 60637, USA
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Abdelilah-Seyfried S, Ola R. Shear stress and pathophysiological PI3K involvement in vascular malformations. J Clin Invest 2024; 134:e172843. [PMID: 38747293 PMCID: PMC11093608 DOI: 10.1172/jci172843] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/19/2024] Open
Abstract
Molecular characterization of vascular anomalies has revealed that affected endothelial cells (ECs) harbor gain-of-function (GOF) mutations in the gene encoding the catalytic α subunit of PI3Kα (PIK3CA). These PIK3CA mutations are known to cause solid cancers when occurring in other tissues. PIK3CA-related vascular anomalies, or "PIKopathies," range from simple, i.e., restricted to a particular form of malformation, to complex, i.e., presenting with a range of hyperplasia phenotypes, including the PIK3CA-related overgrowth spectrum. Interestingly, development of PIKopathies is affected by fluid shear stress (FSS), a physiological stimulus caused by blood or lymph flow. These findings implicate PI3K in mediating physiological EC responses to FSS conditions characteristic of lymphatic and capillary vessel beds. Consistent with this hypothesis, increased PI3K signaling also contributes to cerebral cavernous malformations, a vascular disorder that affects low-perfused brain venous capillaries. Because the GOF activity of PI3K and its signaling partners are excellent drug targets, understanding PIK3CA's role in the development of vascular anomalies may inform therapeutic strategies to normalize EC responses in the diseased state. This Review focuses on PIK3CA's role in mediating EC responses to FSS and discusses current understanding of PIK3CA dysregulation in a range of vascular anomalies that particularly affect low-perfused regions of the vasculature. We also discuss recent surprising findings linking increased PI3K signaling to fast-flow arteriovenous malformations in hereditary hemorrhagic telangiectasias.
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Affiliation(s)
| | - Roxana Ola
- Experimental Pharmacology Mannheim, European Center for Angioscience, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
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9
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Chandurkar MK, Mittal N, Royer-Weeden SP, Lehmann SD, Michels EB, Haarman SE, Severance SA, Rho Y, Han SJ. Transient low shear-stress preconditioning influences long-term endothelial traction and alignment under high shear flow. Am J Physiol Heart Circ Physiol 2024; 326:H1180-H1192. [PMID: 38457352 PMCID: PMC11649189 DOI: 10.1152/ajpheart.00067.2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2024] [Revised: 03/01/2024] [Accepted: 03/03/2024] [Indexed: 03/10/2024]
Abstract
Endothelial cells (ECs) within the vascular system encounter fluid shear stress (FSS). High, laminar FSS promotes vasodilation and anti-inflammatory responses, whereas low or disturbed FSS induces dysfunction and inflammation. However, the adaptation of endothelial cells (ECs) to dynamically changing FSS patterns remains underexplored. Here, by combining traction force microscopy with a custom flow chamber, we examined human umbilical vein endothelial cells adapting their traction during transitions from short-term low shear to long-term high shear stress. We discovered that the initial low FSS elevates the traction by only half of the amount in response to direct high FSS even after flow changes to high FSS. However, in the long term under high FSS, the flow started with low FSS triggers a substantial second rise in traction for over 10 h. In contrast, the flow started directly with high FSS results in a quick traction surge followed by a huge reduction below the baseline traction in <30 min. Importantly, we find that the orientation of traction vectors is steered by initial shear exposure. Using Granger causality analysis, we show that the traction that aligns in the flow direction under direct high FSS functionally causes cell alignment toward the flow direction. However, EC traction that orients perpendicular to the flow that starts with temporary low FSS functionally causes cell orientation perpendicular to the flow. Taken together, our findings elucidate the significant influence of initial short-term low FSS on lasting changes in endothelial traction that induces EC alignment.NEW & NOTEWORTHY In our study, we uncover that preconditioning with low shear stress yields enduring impacts on endothelial cell traction and orientation, persisting even after transitioning to high-shear conditions. Using Granger causality analysis, we demonstrate a functional link between the direction of cell traction and subsequent cellular alignment across varying shear environments.
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Affiliation(s)
- Mohanish K Chandurkar
- Department of Biomedical Engineering, Michigan Technological University, Houghton, Michigan, United States
- Health Research Institute, Michigan Technological University, Houghton, Michigan, United States
| | - Nikhil Mittal
- Department of Biomedical Engineering, Michigan Technological University, Houghton, Michigan, United States
- Health Research Institute, Michigan Technological University, Houghton, Michigan, United States
| | - Shaina P Royer-Weeden
- Department of Biomedical Engineering, Michigan Technological University, Houghton, Michigan, United States
- Health Research Institute, Michigan Technological University, Houghton, Michigan, United States
| | - Steven D Lehmann
- Department of Biomedical Engineering, Michigan Technological University, Houghton, Michigan, United States
| | - Etienne B Michels
- Department of Biomedical Engineering, Michigan Technological University, Houghton, Michigan, United States
| | - Samuel E Haarman
- Department of Biomedical Engineering, Michigan Technological University, Houghton, Michigan, United States
- Health Research Institute, Michigan Technological University, Houghton, Michigan, United States
| | - Scott A Severance
- Department of Biomedical Engineering, Michigan Technological University, Houghton, Michigan, United States
| | - Yeonwoo Rho
- Department of Mathematical Sciences, Michigan Technological University, Houghton, Michigan, United States
| | - Sangyoon J Han
- Department of Biomedical Engineering, Michigan Technological University, Houghton, Michigan, United States
- Health Research Institute, Michigan Technological University, Houghton, Michigan, United States
- Department of Mechanical Engineering and Engineering Mechanics, Michigan Technological University, Houghton, Michigan, United States
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10
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LUO X, JIAN W. Different roles of endothelial cell-derived fibronectin and plasma fibronectin in endothelial dysfunction. Turk J Med Sci 2023; 53:1667-1677. [PMID: 38813506 PMCID: PMC10760598 DOI: 10.55730/1300-0144.5735] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2023] [Revised: 12/12/2023] [Accepted: 10/25/2023] [Indexed: 05/31/2024] Open
Abstract
Background/aim Atherosclerosis is significantly influenced by endothelial cell activation and dysfunction. Studies have demonstrated the substantial presence of fibronectin (Fn) within atherosclerotic plaques, promoting endothelial inflammation and activation. However, cellular Fn (cFn) secreted by various cell types, including endothelial cells and smooth muscle cells, and plasma Fn (pFn) produced by hepatocytes. They are distinct forms of Fn that differ in both structure and function. The specific contribution of different types of Fn in promoting endothelial cell activation and dysfunction remain uncertain. Therefore, this study aimed to investigate the respective roles of pFn and endothelial cell-derived Fn (FnEC) in promoting endothelial cell activation and dysfunction. Materials and methods Initially, endothelial cell injury was induced by exposing the cells to oxidized low-density lipoprotein (ox-LDL) and subsequently we generated a mutant strain of aortic endothelial cells with Fn knockdown (FnEC-KD). The impact of the FnEC-KD arel the addition of pFn on the expression levels of inflammatory factors, vasoconstrictors, and diastolic factors were compared. Results The results showed that the FnEC-KD significantly inhibited ox-LDL-induced intercellular adhesion molecule 1 (ICAM-1, p < 0.05), vascular cell adhesion molecule (VCAM-1, p < 0.05), and endothelin (p < 0.05) expression, and nuclear factor kappa-B (NFκB, p < 0.05) activation. These results implied that FnEC-KD inhibited both endothelial cell activation and dysfunction. Surprisingly, the addition of pFn significantly inhibited the ox-LDL-induced ICAM-1 (p < 0.05), VCAM-1 (p < 0.05), and endothelin (p < 0.05) expression and NFκB (p < 0.05) activation. Implying that pFn inhibits endothelial cell activation and dysfunction. Additionally, the study revealed that ox-LDL stimulation enhanced the production of excessive nitric oxide, leading to severe endothelial cell damage. Conclusion Aortic FnEC promotes endothelial cell activation and endothelial dysfunction, whereas pFn inhibits ox-LDL-induced endothelial cell activation and endothelial dysfunction.
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Affiliation(s)
- Xiaoxin LUO
- Department of Traditional Chinese Medicine Diagnostics, Faculty of Traditional Chinese Medicine, Hunan University of Chinese Medicine, Changsha,
China
| | - Weixiong JIAN
- Department of Traditional Chinese Medicine Diagnostics, Faculty of Traditional Chinese Medicine, Hunan University of Chinese Medicine, Changsha,
China
- Department of National Key Discipline of Traditional Chinese Medicine Diagnostics and Hunan Provincial Key Laboratory, Faculty of Traditional Chinese Medicine, Hunan University of Chinese Medicine, Changsha,
China
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11
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Mannion AJ, Holmgren L. Nuclear mechanosensing of the aortic endothelium in health and disease. Dis Model Mech 2023; 16:dmm050361. [PMID: 37909406 PMCID: PMC10629673 DOI: 10.1242/dmm.050361] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2023] Open
Abstract
The endothelium, the monolayer of endothelial cells that line blood vessels, is exposed to a number of mechanical forces, including frictional shear flow, pulsatile stretching and changes in stiffness influenced by extracellular matrix composition. These forces are sensed by mechanosensors that facilitate their transduction to drive appropriate adaptation of the endothelium to maintain vascular homeostasis. In the aorta, the unique architecture of the vessel gives rise to changes in the fluid dynamics, which, in turn, shape cellular morphology, nuclear architecture, chromatin dynamics and gene regulation. In this Review, we discuss recent work focusing on how differential mechanical forces exerted on endothelial cells are sensed and transduced to influence their form and function in giving rise to spatial variation to the endothelium of the aorta. We will also discuss recent developments in understanding how nuclear mechanosensing is implicated in diseases of the aorta.
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Affiliation(s)
- Aarren J. Mannion
- Department of Oncology-Pathology, Karolinska Institute, Stockholm 171 64, Sweden
| | - Lars Holmgren
- Department of Oncology-Pathology, Karolinska Institute, Stockholm 171 64, Sweden
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12
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McQueen A, Warboys CM. Mechanosignalling pathways that regulate endothelial barrier function. Curr Opin Cell Biol 2023; 84:102213. [PMID: 37531894 DOI: 10.1016/j.ceb.2023.102213] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2023] [Revised: 06/27/2023] [Accepted: 07/04/2023] [Indexed: 08/04/2023]
Abstract
Blood vessels are lined by a single layer of endothelial cells that provide a barrier between circulating plasma and the underlying tissue. Permeability of endothelial cells is tightly regulated, and increased permeability is associated with a number of diseases including atherosclerosis. Endothelial cells are continuously exposed to mechanical forces exerted by flowing blood and are particularly sensitive to shear stress, which is a key determinant of endothelial function. Undisturbed flow promotes endothelial resilience and reduces permeability to macromolecules whereas disturbed flow promotes endothelial dysfunction and barrier disruption. This review will outline recent advances in our understanding of how disturbed and undisturbed flow regulate paracellular and transcellular permeability and will highlight potential cellular targets that could form the basis of therapies to limit the development of cardiovascular disease.
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Affiliation(s)
- Anna McQueen
- Department of Comparative Biomedical Sciences, Royal Veterinary College, Royal College Street, London, NW1 0NN, UK
| | - Christina M Warboys
- Department of Comparative Biomedical Sciences, Royal Veterinary College, Royal College Street, London, NW1 0NN, UK.
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13
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Fonseca CG, Silvério V, Barata D, Giese W, Gerhardt H, Cardoso S, Franco CA. A 96-wells fluidic system for high-throughput screenings under laminar high wall shear stress conditions. MICROSYSTEMS & NANOENGINEERING 2023; 9:114. [PMID: 37719414 PMCID: PMC10504069 DOI: 10.1038/s41378-023-00589-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 03/20/2023] [Revised: 06/14/2023] [Accepted: 07/26/2023] [Indexed: 09/19/2023]
Abstract
The ability of endothelial cells to respond to blood flow is fundamental for the correct formation and maintenance of a functional and hierarchically organized vascular network. Defective flow responses, in particular related to high flow conditions, have been associated with atherosclerosis, stroke, arteriovenous malformations, and neurodegenerative diseases. Yet, the molecular mechanisms involved in high flow response are still poorly understood. Here, we described the development and validation of a 96-wells fluidic system, with interchangeable cell culture and fluidics, to perform high-throughput screenings under laminar high-flow conditions. We demonstrated that endothelial cells in our newly developed 96-wells fluidic system respond to fluid flow-induced shear stress by aligning along the flow direction and increasing the levels of KLF2 and KLF4. We further demonstrate that our 96-wells fluidic system allows for efficient gene knock-down compatible with automated liquid handling for high-throughput screening platforms. Overall, we propose that this modular 96-well fluidic system is an excellent platform to perform genome-wide and/or drug screenings to identify the molecular mechanisms involved in the responses of endothelial cells to high wall shear stress.
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Affiliation(s)
- Catarina Gonçalves Fonseca
- Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal
| | - Vânia Silvério
- INESC Microsistemas and Nanotecnologias, INESC-MN, Lisboa, Portugal
- Department of Physics, Instituto Superior Técnico, Universidade de Lisboa, Lisboa, Portugal
| | - David Barata
- Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal
| | - Wolfgang Giese
- Max Delbrück Center for Molecular Medicine, Berlin, Germany
- DZHK (German Centre for Cardiovascular Research), Partner Site Berlin, Berlin, Germany
| | - Holger Gerhardt
- Max Delbrück Center for Molecular Medicine, Berlin, Germany
- DZHK (German Centre for Cardiovascular Research), Partner Site Berlin, Berlin, Germany
- Charité – Universitätsmedizin Berlin, Berlin, Germany
| | - Susana Cardoso
- INESC Microsistemas and Nanotecnologias, INESC-MN, Lisboa, Portugal
- Department of Physics, Instituto Superior Técnico, Universidade de Lisboa, Lisboa, Portugal
| | - Claudio Areias Franco
- Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal
- Universidade Católica Portuguesa, Católica Medical School, Católica Biomedical Research Centre, Lisbon, Portugal
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14
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Xu Z, Chen Y, Wang Y, Han W, Xu W, Liao X, Zhang T, Wang G. Matrix stiffness, endothelial dysfunction and atherosclerosis. Mol Biol Rep 2023; 50:7027-7041. [PMID: 37382775 DOI: 10.1007/s11033-023-08502-5] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2022] [Accepted: 04/28/2023] [Indexed: 06/30/2023]
Abstract
Atherosclerosis (AS) is the leading cause of the human cardiovascular diseases (CVDs). Endothelial dysfunction promotes the monocytes infiltration and inflammation that participate fundamentally in atherogenesis. Endothelial cells (EC) have been recognized as mechanosensitive cells and have different responses to distinct mechanical stimuli. Emerging evidence shows matrix stiffness-mediated EC dysfunction plays a vital role in vascular disease, but the underlying mechanisms are not yet completely understood. This article aims to summarize the effect of matrix stiffness on the pro-atherosclerotic characteristics of EC including morphology, rigidity, biological behavior and function as well as the related mechanical signal. The review also discusses and compares the contribution of matrix stiffness-mediated phagocytosis of macrophages and EC to AS progression. These advances in our understanding of the relationship between matrix stiffness and EC dysfunction open the avenues to improve the prevention and treatment of now-ubiquitous atherosclerotic diseases.
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Affiliation(s)
- Zichen Xu
- Key Laboratory for Biorheological Science and Technology of Ministry of Education, State and Local Joint Engineering Laboratory for Vascular Implants, Bioengineering College of Chongqing University, Chongqing, 400030, China
| | - Yi Chen
- Chongqing Engineering Laboratory of Nano/Micro Biomedical Detection, Chongqing Key Laboratory of Nano/Micro Composite Material and Device, School of Metallurgy and Materials Engineering, Chongqing University of Science and Technology, Chongqing, 401331, China
| | - Yi Wang
- College of Basic Medical Sciences, Chongqing Medical University, Chongqing, 400016, China
| | - Wenbo Han
- Key Laboratory for Biorheological Science and Technology of Ministry of Education, State and Local Joint Engineering Laboratory for Vascular Implants, Bioengineering College of Chongqing University, Chongqing, 400030, China
| | - Wenfeng Xu
- Chongqing Engineering Laboratory of Nano/Micro Biomedical Detection, Chongqing Key Laboratory of Nano/Micro Composite Material and Device, School of Metallurgy and Materials Engineering, Chongqing University of Science and Technology, Chongqing, 401331, China
| | - Xiaoling Liao
- Chongqing Engineering Laboratory of Nano/Micro Biomedical Detection, Chongqing Key Laboratory of Nano/Micro Composite Material and Device, School of Metallurgy and Materials Engineering, Chongqing University of Science and Technology, Chongqing, 401331, China
| | - Tao Zhang
- Chongqing Engineering Laboratory of Nano/Micro Biomedical Detection, Chongqing Key Laboratory of Nano/Micro Composite Material and Device, School of Metallurgy and Materials Engineering, Chongqing University of Science and Technology, Chongqing, 401331, China.
| | - Guixue Wang
- Key Laboratory for Biorheological Science and Technology of Ministry of Education, State and Local Joint Engineering Laboratory for Vascular Implants, Bioengineering College of Chongqing University, Chongqing, 400030, China.
- Bioengineering College of Chongqing University, NO.174, Shazheng Street, Shapingba District, Chongqing, 400030, PR China.
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15
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Sendo S, Kiosses WB, Yang S, Wu DJ, Lee DWK, Liu L, Aschner Y, Vela AJ, Downey GP, Santelli E, Bottini N. Clustering of phosphatase RPTPα promotes Src signaling and the arthritogenic action of synovial fibroblasts. Sci Signal 2023; 16:eabn8668. [PMID: 37402225 PMCID: PMC10544828 DOI: 10.1126/scisignal.abn8668] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2021] [Accepted: 06/15/2023] [Indexed: 07/06/2023]
Abstract
Receptor-type protein phosphatase α (RPTPα) promotes fibroblast-dependent arthritis and fibrosis, in part, by enhancing the activation of the kinase SRC. Synovial fibroblasts lining joint tissue mediate inflammation and tissue damage, and their infiltration into adjacent tissues promotes disease progression. RPTPα includes an ectodomain and two intracellular catalytic domains (D1 and D2) and, in cancer cells, undergoes inhibitory homodimerization, which is dependent on a D1 wedge motif. Through single-molecule localization and labeled molecule interaction microscopy of migrating synovial fibroblasts, we investigated the role of RPTPα dimerization in the activation of SRC, the migration of synovial fibroblasts, and joint damage in a mouse model of arthritis. RPTPα clustered with other RPTPα and with SRC molecules in the context of actin-rich structures. A known dimerization-impairing mutation in the wedge motif (P210L/P211L) and the deletion of the D2 domain reduced RPTPα-RPTPα clustering; however, it also unexpectedly reduced RPTPα-SRC association. The same mutations also reduced recruitment of RPTPα to actin-rich structures and inhibited SRC activation and cellular migration. An antibody against the RPTPα ectodomain that prevented the clustering of RPTPα also inhibited RPTPα-SRC association and SRC activation and attenuated fibroblast migration and joint damage in arthritic mice. A catalytically inactivating RPTPα-C469S mutation protected mice from arthritis and reduced SRC activation in synovial fibroblasts. We conclude that RPTPα clustering retains it to actin-rich structures to promote SRC-mediated fibroblast migration and can be modulated through the extracellular domain.
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Affiliation(s)
- Sho Sendo
- Dept. of Medicine, University of California San Diego, La Jolla, CA 92093
| | - William B. Kiosses
- Dept. of Medicine, University of California San Diego, La Jolla, CA 92093
- La Jolla Institute for Immunology, La Jolla, CA 92037
| | - Shen Yang
- Dept. of Medicine, University of California San Diego, La Jolla, CA 92093
| | - Dennis J. Wu
- Dept. of Medicine, University of California San Diego, La Jolla, CA 92093
| | - Daniel W. K. Lee
- Dept. of Medicine, University of California San Diego, La Jolla, CA 92093
| | - Lin Liu
- Dept. of Medicine, University of California San Diego, La Jolla, CA 92093
| | - Yael Aschner
- Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine, University of Colorado, Aurora, Colorado
| | - Allison J. Vela
- Dept. of Medicine, University of California San Diego, La Jolla, CA 92093
| | - Gregory P. Downey
- Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, National Jewish Health, Denver, Colorado
- Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine, University of Colorado, Aurora, Colorado
- Department of Biomedical Research, National Jewish Health, Denver, Colorado
- Department of Immunology and Microbiology, University of Colorado, Aurora, Colorado
- Department of Pediatrics, National Jewish Health, Denver, Colorado
| | - Eugenio Santelli
- Dept. of Medicine, University of California San Diego, La Jolla, CA 92093
| | - Nunzio Bottini
- Dept. of Medicine, University of California San Diego, La Jolla, CA 92093
- Department of Medicine, Kao Autoimmunity Institute, Cedars Sinai Medical Center, Los Angeles, CA, USA
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16
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Davis MJ, Earley S, Li YS, Chien S. Vascular mechanotransduction. Physiol Rev 2023; 103:1247-1421. [PMID: 36603156 PMCID: PMC9942936 DOI: 10.1152/physrev.00053.2021] [Citation(s) in RCA: 90] [Impact Index Per Article: 45.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2021] [Revised: 09/26/2022] [Accepted: 10/04/2022] [Indexed: 01/07/2023] Open
Abstract
This review aims to survey the current state of mechanotransduction in vascular smooth muscle cells (VSMCs) and endothelial cells (ECs), including their sensing of mechanical stimuli and transduction of mechanical signals that result in the acute functional modulation and longer-term transcriptomic and epigenetic regulation of blood vessels. The mechanosensors discussed include ion channels, plasma membrane-associated structures and receptors, and junction proteins. The mechanosignaling pathways presented include the cytoskeleton, integrins, extracellular matrix, and intracellular signaling molecules. These are followed by discussions on mechanical regulation of transcriptome and epigenetics, relevance of mechanotransduction to health and disease, and interactions between VSMCs and ECs. Throughout this review, we offer suggestions for specific topics that require further understanding. In the closing section on conclusions and perspectives, we summarize what is known and point out the need to treat the vasculature as a system, including not only VSMCs and ECs but also the extracellular matrix and other types of cells such as resident macrophages and pericytes, so that we can fully understand the physiology and pathophysiology of the blood vessel as a whole, thus enhancing the comprehension, diagnosis, treatment, and prevention of vascular diseases.
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Affiliation(s)
- Michael J Davis
- Department of Medical Pharmacology and Physiology, University of Missouri, Columbia, Missouri
| | - Scott Earley
- Department of Pharmacology, University of Nevada, Reno, Nevada
| | - Yi-Shuan Li
- Department of Bioengineering, University of California, San Diego, California
- Institute of Engineering in Medicine, University of California, San Diego, California
| | - Shu Chien
- Department of Bioengineering, University of California, San Diego, California
- Institute of Engineering in Medicine, University of California, San Diego, California
- Department of Medicine, University of California, San Diego, California
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17
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Xie N, Xiao C, Shu Q, Cheng B, Wang Z, Xue R, Wen Z, Wang J, Shi H, Fan D, Liu N, Xu F. Cell response to mechanical microenvironment cues via Rho signaling: From mechanobiology to mechanomedicine. Acta Biomater 2023; 159:1-20. [PMID: 36717048 DOI: 10.1016/j.actbio.2023.01.039] [Citation(s) in RCA: 36] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2022] [Revised: 01/10/2023] [Accepted: 01/17/2023] [Indexed: 01/30/2023]
Abstract
Mechanical cues in the cell microenvironment such as those from extracellular matrix properties, stretching, compression and shear stress, play a critical role in maintaining homeostasis. Upon sensing mechanical stimuli, cells can translate these external forces into intracellular biochemical signals to regulate their cellular behaviors, but the specific mechanisms of mechanotransduction at the molecular level remain elusive. As a subfamily of the Ras superfamily, Rho GTPases have been recognized as key intracellular mechanotransduction mediators that can regulate multiple cell activities such as proliferation, migration and differentiation as well as biological processes such as cytoskeletal dynamics, metabolism, and organ development. However, the upstream mechanosensors for Rho proteins and downstream effectors that respond to Rho signal activation have not been well illustrated. Moreover, Rho-mediated mechanical signals in previous studies are highly context-dependent. In this review, we systematically summarize the types of mechanical cues in the cell microenvironment and provide recent advances on the roles of the Rho-based mechanotransduction in various cell activities, physiological processes and diseases. Comprehensive insights into the mechanical roles of Rho GTPase partners would open a new paradigm of mechanomedicine for a variety of diseases. STATEMENT OF SIGNIFICANCE: In this review, we highlight the critical role of Rho GTPases as signal mediators to respond to physical cues in microenvironment. This article will add a distinct contribution to this set of knowledge by intensively addressing the relationship between Rho signaling and mechanobiology/mechanotransduction/mechanomedcine. This topic has not been discussed by the journal, nor has it yet been developed by the field. The comprehensive picture that will develop, from molecular mechanisms and engineering methods to disease treatment strategies, represents an important and distinct contribution to the field. We hope that this review would help researchers in various fields, especially clinicians, oncologists and bioengineers, who study Rho signal pathway and mechanobiology/mechanotransduction, understand the critical role of Rho GTPase in mechanotransduction.
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Affiliation(s)
- Ning Xie
- Department of Gastroenterology, The Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi 710049, China; Bioinspired Engineering and Biomechanics Center (BEBC), Xi'an Jiaotong University, Xi'an, Shaanxi 710049, China; The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, Shaanxi 710049, China
| | - Cailan Xiao
- Department of Gastroenterology, The Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi 710049, China; Bioinspired Engineering and Biomechanics Center (BEBC), Xi'an Jiaotong University, Xi'an, Shaanxi 710049, China; The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, Shaanxi 710049, China
| | - Qiuai Shu
- Department of Gastroenterology, The Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi 710049, China
| | - Bo Cheng
- Bioinspired Engineering and Biomechanics Center (BEBC), Xi'an Jiaotong University, Xi'an, Shaanxi 710049, China; The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, Shaanxi 710049, China
| | - Ziwei Wang
- Department of Gastroenterology, The Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi 710049, China
| | - Runxin Xue
- Department of Gastroenterology, The Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi 710049, China
| | - Zhang Wen
- Department of Gastroenterology, The Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi 710049, China
| | - Jinhai Wang
- Department of Gastroenterology, The Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi 710049, China
| | - Haitao Shi
- Department of Gastroenterology, The Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi 710049, China
| | - Daiming Fan
- State Key Laboratory of Cancer Biology and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an Shaanxi 710049, China.
| | - Na Liu
- Department of Gastroenterology, The Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi 710049, China; Bioinspired Engineering and Biomechanics Center (BEBC), Xi'an Jiaotong University, Xi'an, Shaanxi 710049, China; The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, Shaanxi 710049, China.
| | - Feng Xu
- Bioinspired Engineering and Biomechanics Center (BEBC), Xi'an Jiaotong University, Xi'an, Shaanxi 710049, China; The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, Shaanxi 710049, China.
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18
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Tian G, Ren T. Mechanical stress regulates the mechanotransduction and metabolism of cardiac fibroblasts in fibrotic cardiac diseases. Eur J Cell Biol 2023; 102:151288. [PMID: 36696810 DOI: 10.1016/j.ejcb.2023.151288] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2022] [Revised: 01/17/2023] [Accepted: 01/18/2023] [Indexed: 01/20/2023] Open
Abstract
Fibrotic cardiac diseases are characterized by myocardial fibrosis that results in maladaptive cardiac remodeling. Cardiac fibroblasts (CFs) are the main cell type responsible for fibrosis. In response to stress or injury, intrinsic CFs develop into myofibroblasts and produce excess extracellular matrix (ECM) proteins. Myofibroblasts are mechanosensitive cells that can detect changes in tissue stiffness and respond accordingly. Previous studies have revealed that some mechanical stimuli control fibroblast behaviors, including ECM formation, cell migration, and other phenotypic traits. Further, metabolic alteration is reported to regulate fibrotic signaling cascades, such as the transforming growth factor-β pathway and ECM deposition. However, the relationship between metabolic changes and mechanical stress during fibroblast-to-myofibroblast transition remains unclear. This review aims to elaborate on the crosstalk between mechanical stress and metabolic changes during the pathological transition of cardiac fibroblasts.
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Affiliation(s)
- Geer Tian
- Department of Cardiology of The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, PR China; Cardiovascular Key Laboratory of Zhejiang Province, Hangzhou, PR China; Binjiang Institute of Zhejiang University, 66 Dongxin Road, Hangzhou 310053, PR China
| | - Tanchen Ren
- Department of Cardiology of The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, PR China; Cardiovascular Key Laboratory of Zhejiang Province, Hangzhou, PR China.
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19
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Aguilar VM, Paul A, Lazarko D, Levitan I. Paradigms of endothelial stiffening in cardiovascular disease and vascular aging. Front Physiol 2023; 13:1081119. [PMID: 36714307 PMCID: PMC9874005 DOI: 10.3389/fphys.2022.1081119] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2022] [Accepted: 12/22/2022] [Indexed: 01/13/2023] Open
Abstract
Endothelial cells, the inner lining of the blood vessels, are well-known to play a critical role in vascular function, while endothelial dysfunction due to different cardiovascular risk factors or accumulation of disruptive mechanisms that arise with aging lead to cardiovascular disease. In this review, we focus on endothelial stiffness, a fundamental biomechanical property that reflects cell resistance to deformation. In the first part of the review, we describe the mechanisms that determine endothelial stiffness, including RhoA-dependent contractile response, actin architecture and crosslinking, as well as the contributions of the intermediate filaments, vimentin and lamin. Then, we review the factors that induce endothelial stiffening, with the emphasis on mechanical signals, such as fluid shear stress, stretch and stiffness of the extracellular matrix, which are well-known to control endothelial biomechanics. We also describe in detail the contribution of lipid factors, particularly oxidized lipids, that were also shown to be crucial in regulation of endothelial stiffness. Furthermore, we discuss the relative contributions of these two mechanisms of endothelial stiffening in vasculature in cardiovascular disease and aging. Finally, we present the current state of knowledge about the role of endothelial stiffening in the disruption of endothelial cell-cell junctions that are responsible for the maintenance of the endothelial barrier.
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Affiliation(s)
- Victor M. Aguilar
- Department of Medicine, Division of Pulmonary and Critical Care, College of Medicine, University of Illinois at Chicago, Chicago, IL, United States
- Richard and Loan Hill Department of Biomedical Engineering, University of Illinois at Chicago, Chicago, IL, United States
| | - Amit Paul
- Department of Medicine, Division of Pulmonary and Critical Care, College of Medicine, University of Illinois at Chicago, Chicago, IL, United States
| | - Dana Lazarko
- Department of Medicine, Division of Pulmonary and Critical Care, College of Medicine, University of Illinois at Chicago, Chicago, IL, United States
| | - Irena Levitan
- Department of Medicine, Division of Pulmonary and Critical Care, College of Medicine, University of Illinois at Chicago, Chicago, IL, United States
- Richard and Loan Hill Department of Biomedical Engineering, University of Illinois at Chicago, Chicago, IL, United States
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20
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Min S, Tao W, Ding D, Zhang X, Zhao S, Zhang Y, Liu X, Gao K, Liu S, Li L, Hou M, Li Y. Tetramethylpyrazine ameliorates acute lung injury by regulating the Rac1/LIMK1 signaling pathway. Front Pharmacol 2023; 13:1005014. [PMID: 36686718 PMCID: PMC9859661 DOI: 10.3389/fphar.2022.1005014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2022] [Accepted: 12/20/2022] [Indexed: 01/07/2023] Open
Abstract
Acute lung injury (ALI) is a respiratory disorder characterized by severe inflammation of the alveoli and lung parenchyma. Tetramethylpyrazine (TMP), the main active compound in Ligusticum chuanxiong Hort (LC), can protect against lipopolysaccharide (LPS)-induced ALI. Our study aimed to investigate how TMP protects the endothelial cell barrier in pulmonary capillaries. We administered TMP intraperitoneally at different doses and found that acute lung injury in mice was improved, but not in a dose-dependent manner. TMP toxicity was tested in vitro. We observed that LPS-induced cytoskeletal remodeling was inhibited by TMP. Murine ALI was induced as follows: For the 1st hit, LPS (2 mg/kg) was injected intraperitoneally; after 16 h, for the 2nd hit, LPS (4 mg/kg) was instilled intratracheally. The mice in treatment groups had TMP or dexamethasone administered intraperitoneally 30 min prior to the 1st hit and 30 min past the 2nd hit. Mice were euthanized 24 h after the last injecting. We measured protein and mRNA levels using enzyme-linked immunosorbent assay (ELISA) and reverse transcriptase real-time PCR (RT-qPCR), respectively. The ultrastructural analysis was performed with transmission electron microscopy (TEM) and the cytoskeleton was observed by immunofluorescence. Immunohistochemistry and Western blotting were used to detect protein expression in the Rac1/LIMK1/ZO-1/occludin signal pathway. The results showed that TMP treatment decreased inflammatory cell infiltration and alleviated LPS-induced damage in lung tissue. Also, TMP significantly inhibited the Rac1/LIMK1/ZO-1/occludin signaling pathway. Our findings show that using TMP during sepsis can protect the pulmonary microvascular endothelial cell barrier and suppress inflammation. Therefore, TMP may have a promising therapeutic role in preventing acute lung injury from sepsis.
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Affiliation(s)
- Simin Min
- School of medicine and health engineering, Changzhou university, Changzhou, Jiangsu, China,Department of Pathophysiology, Bengbu Medical College, Bengbu, Anhui, China
| | - Weiting Tao
- Department of Pathophysiology, Bengbu Medical College, Bengbu, Anhui, China
| | - Dushan Ding
- Department of Pathophysiology, Bengbu Medical College, Bengbu, Anhui, China
| | - Xiaonan Zhang
- Department of Pathophysiology, Bengbu Medical College, Bengbu, Anhui, China
| | - Shidi Zhao
- Department of Pathophysiology, Bengbu Medical College, Bengbu, Anhui, China
| | - Yong Zhang
- Department of Respiratory, The First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui, China
| | - Xiaojie Liu
- Department of Respiratory, The First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui, China
| | - Kefei Gao
- Department of Respiratory, The First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui, China
| | - Saisai Liu
- Department of Pathophysiology, Bengbu Medical College, Bengbu, Anhui, China
| | - Li Li
- Department of Pathophysiology, Bengbu Medical College, Bengbu, Anhui, China
| | - Min Hou
- Department of Pharmaceutical Engineering, Bengbu Medical College, Bengbu, Anhui, China
| | - Yan Li
- School of medicine and health engineering, Changzhou university, Changzhou, Jiangsu, China,Department of Pathophysiology, Bengbu Medical College, Bengbu, Anhui, China,*Correspondence: Yan Li,
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21
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Du R, Li D, Zhu M, Zheng L, Ren K, Han D, Li L, Ji J, Fan Y. Cell senescence alters responses of porcine trabecular meshwork cells to shear stress. Front Cell Dev Biol 2022; 10:1083130. [PMID: 36478743 PMCID: PMC9721263 DOI: 10.3389/fcell.2022.1083130] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2022] [Accepted: 11/04/2022] [Indexed: 10/05/2024] Open
Abstract
Mechanical microenvironment and cellular senescence of trabecular meshwork cells (TMCs) are suspected to play a vital role in primary open-angle glaucoma pathogenesis. However, central questions remain about the effect of shear stress on TMCs and how aging affects this process. We have investigated the effect of shear stress on the biomechanical properties and extracellular matrix regulation of normal and senescent TMCs. We found a more significant promotion of Fctin formation, a more obvious realignment of F-actin fibers, and a more remarkable increase in the stiffness of normal cells in response to the shear stress, in comparison with that of senescent cells. Further, as compared to normal cells, senescent cells show a reduced extracellular matrix turnover after shear stress stimulation, which might be attributed to the different phosphorylation levels of the extracellular signal-regulated kinase. Our results suggest that TMCs are able to sense and respond to the shear stress and cellular senescence undermines the mechanobiological response, which may lead to progressive failure of cellular TM function with age.
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Affiliation(s)
- Ruotian Du
- Key Laboratory of Biomechanics and Mechanobiology of Ministry of Education, Beijing Advanced Innovation Center for Biomedical Engineering, School of Biological Science and Medical Engineering, Beihang University, Beijing, China
| | - Dongyan Li
- Key Laboratory of Biomechanics and Mechanobiology of Ministry of Education, Beijing Advanced Innovation Center for Biomedical Engineering, School of Biological Science and Medical Engineering, Beihang University, Beijing, China
| | - Meng Zhu
- Key Laboratory of Biomechanics and Mechanobiology of Ministry of Education, Beijing Advanced Innovation Center for Biomedical Engineering, School of Biological Science and Medical Engineering, Beihang University, Beijing, China
| | - Lisha Zheng
- Key Laboratory of Biomechanics and Mechanobiology of Ministry of Education, Beijing Advanced Innovation Center for Biomedical Engineering, School of Biological Science and Medical Engineering, Beihang University, Beijing, China
| | - Keli Ren
- Lab for Biological Imaging and Nanomedicine, National Center for Nanoscience and Technology, Beijing, China
| | - Dong Han
- Lab for Biological Imaging and Nanomedicine, National Center for Nanoscience and Technology, Beijing, China
| | - Long Li
- State Key Laboratory of Nonlinear Mechanics and Beijing Key Laboratory of Engineered Construction and Mechanobiology, Institute of Mechanics, Chinese Academy of Sciences, Beijing, China
| | - Jing Ji
- Key Laboratory of Biomechanics and Mechanobiology of Ministry of Education, Beijing Advanced Innovation Center for Biomedical Engineering, School of Biological Science and Medical Engineering, Beihang University, Beijing, China
| | - Yubo Fan
- Key Laboratory of Biomechanics and Mechanobiology of Ministry of Education, Beijing Advanced Innovation Center for Biomedical Engineering, School of Biological Science and Medical Engineering, Beihang University, Beijing, China
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22
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Liu W, Cronin CG, Cao Z, Wang C, Ruan J, Pulikkot S, Hall A, Sun H, Groisman A, Chen Y, Vella AT, Hu L, Liang BT, Fan Z. Nexinhib20 Inhibits Neutrophil Adhesion and β 2 Integrin Activation by Antagonizing Rac-1-Guanosine 5'-Triphosphate Interaction. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2022; 209:1574-1585. [PMID: 36165184 PMCID: PMC9529951 DOI: 10.4049/jimmunol.2101112] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/23/2021] [Accepted: 08/03/2022] [Indexed: 11/07/2022]
Abstract
Neutrophils are critical for mediating inflammatory responses. Inhibiting neutrophil recruitment is an attractive approach for preventing inflammatory injuries, including myocardial ischemia-reperfusion (I/R) injury, which exacerbates cardiomyocyte death after primary percutaneous coronary intervention in acute myocardial infarction. In this study, we found out that a neutrophil exocytosis inhibitor Nexinhib20 inhibits not only exocytosis but also neutrophil adhesion by limiting β2 integrin activation. Using a microfluidic chamber, we found that Nexinhib20 inhibited IL-8-induced β2 integrin-dependent human neutrophil adhesion under flow. Using a dynamic flow cytometry assay, we discovered that Nexinhib20 suppresses intracellular calcium flux and β2 integrin activation after IL-8 stimulation. Western blots of Ras-related C3 botulinum toxin substrate 1 (Rac-1)-GTP pull-down assays confirmed that Nexinhib20 inhibited Rac-1 activation in leukocytes. An in vitro competition assay showed that Nexinhib20 antagonized the binding of Rac-1 and GTP. Using a mouse model of myocardial I/R injury, Nexinhib20 administration after ischemia and before reperfusion significantly decreased neutrophil recruitment and infarct size. Our results highlight the translational potential of Nexinhib20 as a dual-functional neutrophil inhibitory drug to prevent myocardial I/R injury.
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Affiliation(s)
- Wei Liu
- Department of Immunology, School of Medicine, UConn Health, Farmington, CT
| | - Chunxia G Cronin
- Pat and Jim Calhoun Cardiology Center, School of Medicine, UConn Health, Farmington, CT
| | - Ziming Cao
- Department of Immunology, School of Medicine, UConn Health, Farmington, CT
| | - Chengliang Wang
- Department of Immunology, School of Medicine, UConn Health, Farmington, CT
| | - Jianbin Ruan
- Department of Immunology, School of Medicine, UConn Health, Farmington, CT
| | - Sunitha Pulikkot
- Department of Immunology, School of Medicine, UConn Health, Farmington, CT
| | - Alexxus Hall
- Department of Immunology, School of Medicine, UConn Health, Farmington, CT
| | - Hao Sun
- Department of Medicine, University of California San Diego, La Jolla, CA
| | - Alex Groisman
- Department of Physics, University of California San Diego, La Jolla, CA
| | - Yunfeng Chen
- Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX
- Department of Pathology, University of Texas Medical Branch, Galveston, TX
| | - Anthony T Vella
- Department of Immunology, School of Medicine, UConn Health, Farmington, CT
| | - Liang Hu
- Academy of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China; and
| | - Bruce T Liang
- Pat and Jim Calhoun Cardiology Center, School of Medicine, UConn Health, Farmington, CT;
| | - Zhichao Fan
- Department of Immunology, School of Medicine, UConn Health, Farmington, CT;
- Division of Inflammation Biology, La Jolla Institute for Immunology, La Jolla, CA
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Batta SPR, Rio M, Lebot C, Baron-menguy C, Le Ruz R, Loirand G, Vion A. ARHGEF18 participates in Endothelial Cell Mechano-sensitivity in Response to Flow.. [DOI: 10.1101/2022.09.10.507283] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/27/2023]
Abstract
AbstractHemodynamic forces play an important role in vascular network development and homeostasis. In physiological condition, shear stress generated by laminar flow promotes endothelial cells (EC) health and induces their alignment in the direction of flow. In contrast, altered hemodynamic forces induce endothelial dysfunction and lead to the development of vascular disorders such as atherosclerosis and aneurysms. Following mechano-sensor activation, Rho protein-mediated cytoskeletal rearrangement is one of the first steps in transforming flow-induced forces into intracellular signals in EC via guanine nucleotide exchange factors (RhoGEFs) that mediate the spatio-temporal activation of these Rho proteins. Here we identified ARHGEF18 as a flow-sensitive RhoGEF specifically activating RhoA. Both ARHGEF18 expression and activity were controlled by shear stress level. ARHGEF18 promotes EC adhesion, focal adhesion formation and migration. ARHGEF18 localized to the tight junction by interacting with ZO-1 and participated to shear stress-induced EC elongation and alignment via its nucleotide exchange activity and the activation of p38 MAPK. Our study therefore characterized ARHGEF18 as the first flow-sensitive RhoA GEF in ECs, whose activity is essential for the maintenance of intercellular junctions and a properly organized endothelial monolayer under physiological flow conditions.
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Wang C, Qu K, Wang J, Qin R, Li B, Qiu J, Wang G. Biomechanical regulation of planar cell polarity in endothelial cells. Biochim Biophys Acta Mol Basis Dis 2022; 1868:166495. [PMID: 35850177 DOI: 10.1016/j.bbadis.2022.166495] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 07/09/2022] [Accepted: 07/11/2022] [Indexed: 01/03/2023]
Abstract
Cell polarity refers to the uneven distribution of certain cytoplasmic components in a cell with a spatial order. The planar cell polarity (PCP), the cell aligns perpendicular to the polar plane, in endothelial cells (ECs) has become a research hot spot. The planar polarity of ECs has a positive significance on the regulation of cardiovascular dysfunction, pathological angiogenesis, and ischemic stroke. The endothelial polarity is stimulated and regulated by biomechanical force. Mechanical stimuli promote endothelial polarization and make ECs produce PCP to maintain the normal physiological and biochemical functions. Here, we overview recent advances in understanding the interplay and mechanism between PCP and ECs function involved in mechanical forces, with a focus on PCP signaling pathways and organelles in regulating the polarity of ECs. And then showed the related diseases caused by ECs polarity dysfunction. This study provides new ideas and therapeutic targets for the treatment of endothelial PCP-related diseases.
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Affiliation(s)
- Caihong Wang
- Key Laboratory for Biorheological Science and Technology of Ministry of Education, State and Local Joint Engineering Laboratory for Vascular Implants, Bioengineering College of Chongqing University, Chongqing, China
| | - Kai Qu
- Key Laboratory for Biorheological Science and Technology of Ministry of Education, State and Local Joint Engineering Laboratory for Vascular Implants, Bioengineering College of Chongqing University, Chongqing, China
| | - Jing Wang
- Institute of Food and Nutrition Development, Ministry of Agriculture and Rural Affairs, Beijing, China
| | - Rui Qin
- College of Life Sciences, South-Central University for Nationalities, Wuhan, China
| | - Bingyi Li
- Key Laboratory for Biorheological Science and Technology of Ministry of Education, State and Local Joint Engineering Laboratory for Vascular Implants, Bioengineering College of Chongqing University, Chongqing, China
| | - Juhui Qiu
- Key Laboratory for Biorheological Science and Technology of Ministry of Education, State and Local Joint Engineering Laboratory for Vascular Implants, Bioengineering College of Chongqing University, Chongqing, China.
| | - Guixue Wang
- Key Laboratory for Biorheological Science and Technology of Ministry of Education, State and Local Joint Engineering Laboratory for Vascular Implants, Bioengineering College of Chongqing University, Chongqing, China.
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25
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Choublier N, Taghi M, Menet MC, Le Gall M, Bruce J, Chafey P, Guillonneau F, Moreau A, Denizot C, Parmentier Y, Nakib S, Borderie D, Bouzinba-Segard H, Couraud PO, Bourdoulous S, Declèves X. Exposure of human cerebral microvascular endothelial cells hCMEC/D3 to laminar shear stress induces vascular protective responses. Fluids Barriers CNS 2022; 19:41. [PMID: 35658915 PMCID: PMC9164338 DOI: 10.1186/s12987-022-00344-w] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2021] [Accepted: 05/23/2022] [Indexed: 01/01/2023] Open
Abstract
Endothelial cells (ECs) are constantly submitted in vivo to hemodynamical forces derived from the blood circulation, including shear stress (SS). ECs are able to detect SS and consequently adapt their phenotype, thus affecting many endothelial functions. If a plethora of shear stress-regulated molecular networks have been described in peripheral ECs, less is known about the molecular responses of microvascular brain ECs which constitute the blood-brain barrier (BBB). In this work, we investigated the response of human cerebral microvascular ECs to laminar physiological shear stress using the well characterized hCMEC/D3 cell line. Interestingly, we showed that hCMEC/D3 cells responded to shear stress by aligning perpendicularly to the flow direction, contrary to peripheral endothelial cells which aligned in the flow direction. Whole proteomic profiles were compared between hCMEC/D3 cells cultured either in static condition or under 5 or 10 dyn.cm-2 SS for 3 days. 3592 proteins were identified and expression levels were significantly affected for 3% of them upon both SS conditions. Pathway analyses were performed which revealed that most proteins overexpressed by SS refer to the antioxidant defense, probably mediated by activation of the NRF2 transcriptional factor. Regarding down-regulated proteins, most of them participate to the pro-inflammatory response, cell motility and proliferation. These findings confirm the induction of EC quiescence by laminar physiological SS and reveal a strong protective effect of SS on hCMEC/D3 cells, suggesting a similar effect on the BBB. Our results also showed that SS did not significantly increase expression levels nor did it affect the localization of junctional proteins and did not afect either the functional activity of several ABC transporters (P-glycoprotein and MRPs). This work provides new insights on the response of microvascular brain ECs to SS and on the importance of SS for optimizing in vitro BBB models.
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Affiliation(s)
- Nina Choublier
- INSERM, Optimisation Thérapeutique en Neuropsychopharmacologie, Université Paris Cité, 75006, Paris, France.
| | - Meryam Taghi
- INSERM, Optimisation Thérapeutique en Neuropsychopharmacologie, Université Paris Cité, 75006, Paris, France
| | - Marie-Claude Menet
- Institut de Chimie Physique, CNRS, Université Paris-Saclay, 91405, Orsay, France
| | - Morgane Le Gall
- 3P5 Proteom'IC Facility, Institut Cochin, INSERM, CNRS, Université de Paris, F-75014, Paris, France
| | - Johanna Bruce
- 3P5 Proteom'IC Facility, Institut Cochin, INSERM, CNRS, Université de Paris, F-75014, Paris, France
| | - Philippe Chafey
- 3P5 Proteom'IC Facility, Institut Cochin, INSERM, CNRS, Université de Paris, F-75014, Paris, France
| | - François Guillonneau
- 3P5 Proteom'IC Facility, Institut Cochin, INSERM, CNRS, Université de Paris, F-75014, Paris, France
| | | | | | | | - Samir Nakib
- Service de Biochimie, Hôpital Cochin, Assistance Publique-Hôpitaux de Paris, 75014, Paris, France
| | - Didier Borderie
- Service de Biochimie, Hôpital Cochin, Assistance Publique-Hôpitaux de Paris, 75014, Paris, France
| | - Haniaa Bouzinba-Segard
- CNRS, INSERM, Institut Cochin, Inserm, CNRS, Université Paris Cité, 75014, Paris, France
| | - Pierre-Olivier Couraud
- CNRS, INSERM, Institut Cochin, Inserm, CNRS, Université Paris Cité, 75014, Paris, France
| | - Sandrine Bourdoulous
- CNRS, INSERM, Institut Cochin, Inserm, CNRS, Université Paris Cité, 75014, Paris, France
| | - Xavier Declèves
- INSERM, Optimisation Thérapeutique en Neuropsychopharmacologie, Université Paris Cité, 75006, Paris, France.
- Biologie du Médicament Et Toxicologie, AP-HP, Hôpital Cochin, 75014, Paris, France.
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26
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Dupont S, Wickström SA. Mechanical regulation of chromatin and transcription. Nat Rev Genet 2022; 23:624-643. [DOI: 10.1038/s41576-022-00493-6] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/21/2022] [Indexed: 01/14/2023]
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27
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Endothelial Cell Plasma Membrane Biomechanics Mediates Effects of Pro-Inflammatory Factors on Endothelial Mechanosensors: Vicious Circle Formation in Atherogenic Inflammation. MEMBRANES 2022; 12:membranes12020205. [PMID: 35207126 PMCID: PMC8877251 DOI: 10.3390/membranes12020205] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/10/2021] [Revised: 01/31/2022] [Accepted: 02/03/2022] [Indexed: 02/01/2023]
Abstract
Chronic low-grade vascular inflammation and endothelial dysfunction significantly contribute to the pathogenesis of cardiovascular diseases. In endothelial cells (ECs), anti-inflammatory or pro-inflammatory signaling can be induced by different patterns of the fluid shear stress (SS) exerted by blood flow on ECs. Laminar blood flow with high magnitude is anti-inflammatory, while disturbed flow and laminar flow with low magnitude is pro-inflammatory. Endothelial mechanosensors are the key upstream signaling proteins in SS-induced pro- and anti-inflammatory responses. Being transmembrane proteins, mechanosensors, not only experience fluid SS but also become regulated by the biomechanical properties of the lipid bilayer and the cytoskeleton. We review the apparent effects of pro-inflammatory factors (hypoxia, oxidative stress, hypercholesterolemia, and cytokines) on the biomechanics of the lipid bilayer and the cytoskeleton. An analysis of the available data suggests that the formation of a vicious circle may occur, in which pro-inflammatory cytokines enhance and attenuate SS-induced pro-inflammatory and anti-inflammatory signaling, respectively.
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28
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Lee CF, Carley RE, Butler CA, Morrison AR. Rac GTPase Signaling in Immune-Mediated Mechanisms of Atherosclerosis. Cells 2021; 10:2808. [PMID: 34831028 PMCID: PMC8616135 DOI: 10.3390/cells10112808] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2021] [Revised: 10/15/2021] [Accepted: 10/17/2021] [Indexed: 11/17/2022] Open
Abstract
Coronary artery disease caused by atherosclerosis is a major cause of morbidity and mortality around the world. Data from preclinical and clinical studies support the belief that atherosclerosis is an inflammatory disease that is mediated by innate and adaptive immune signaling mechanisms. This review sought to highlight the role of Rac-mediated inflammatory signaling in the mechanisms driving atherosclerotic calcification. In addition, current clinical treatment strategies that are related to targeting hypercholesterolemia as a critical risk factor for atherosclerotic vascular disease are addressed in relation to the effects on Rac immune signaling and the implications for the future of targeting immune responses in the treatment of calcific atherosclerosis.
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Affiliation(s)
- Cadence F. Lee
- Ocean State Research Institute, Inc., Providence VA Medical Center, Research (151), 830 Chalkstone Avenue, Providence, RI 02908, USA; (C.F.L.); (R.E.C.); (C.A.B.)
- Alpert Medical School, Brown University, Providence, RI 02912, USA
| | - Rachel E. Carley
- Ocean State Research Institute, Inc., Providence VA Medical Center, Research (151), 830 Chalkstone Avenue, Providence, RI 02908, USA; (C.F.L.); (R.E.C.); (C.A.B.)
- Alpert Medical School, Brown University, Providence, RI 02912, USA
| | - Celia A. Butler
- Ocean State Research Institute, Inc., Providence VA Medical Center, Research (151), 830 Chalkstone Avenue, Providence, RI 02908, USA; (C.F.L.); (R.E.C.); (C.A.B.)
- Alpert Medical School, Brown University, Providence, RI 02912, USA
| | - Alan R. Morrison
- Ocean State Research Institute, Inc., Providence VA Medical Center, Research (151), 830 Chalkstone Avenue, Providence, RI 02908, USA; (C.F.L.); (R.E.C.); (C.A.B.)
- Alpert Medical School, Brown University, Providence, RI 02912, USA
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He J, Cui Z, Zhu Y. The role of caveolae in endothelial dysfunction. MEDICAL REVIEW (BERLIN, GERMANY) 2021; 1:78-91. [PMID: 37724072 PMCID: PMC10388784 DOI: 10.1515/mr-2021-0005] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/19/2021] [Accepted: 08/03/2021] [Indexed: 09/20/2023]
Abstract
Caveolae, the specialized cell-surface plasma membrane invaginations which are abundant in endothelial cells, play critical roles in regulating various cellular processes, including cholesterol homeostasis, nitric oxide production, and signal transduction. Endothelial caveolae serve as a membrane platform for compartmentalization, modulation, and integration of signal events associated with endothelial nitric oxide synthase, ATP synthase β, and integrins, which are involved in the regulation of endothelial dysfunction and related cardiovascular diseases, such as atherosclerosis and hypertension. Furthermore, these dynamic microdomains on cell membrane are modulated by various extracellular stimuli, including cholesterol and flow shear stress. In this brief review, we summarize the critical roles of caveolae in the orchestration of endothelial function based on recent findings as well as our work over the past two decades.
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Affiliation(s)
- Jinlong He
- Tianjin Key Laboratory of Metabolic Diseases, The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics and Department of Physiology and Pathophysiology, Tianjin Medical University, Tianjin300070, China
| | - Zhen Cui
- Tianjin Key Laboratory of Metabolic Diseases, The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics and Department of Physiology and Pathophysiology, Tianjin Medical University, Tianjin300070, China
| | - Yi Zhu
- Tianjin Key Laboratory of Metabolic Diseases, The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics and Department of Physiology and Pathophysiology, Tianjin Medical University, Tianjin300070, China
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Endoglin deficiency impairs VEGFR2 but not FGFR1 or TIE2 activation and alters VEGF-mediated cellular responses in human primary endothelial cells. Transl Res 2021; 235:129-143. [PMID: 33894400 PMCID: PMC8328903 DOI: 10.1016/j.trsl.2021.04.005] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/16/2020] [Revised: 03/29/2021] [Accepted: 04/14/2021] [Indexed: 01/23/2023]
Abstract
Hereditary hemorrhagic telangiectasia (HHT) is a genetic disease characterized by vascular dysplasia. Mutations of the endoglin (ENG) gene that encodes a co-receptor of the transforming growth factor β1 signaling pathway cause type I HHT. ENG is primarily expressed in endothelial cells (ECs), but its interaction with other key angiogenic pathways to control angiogenesis has not been well addressed. The aim of this study is to investigate ENG interplay with VEGFR2, FGFR1 and TIE2 in primary human ECs. ENG was knocked-down with siRNA in human umbilical vein ECs (HUVECs) and human lung microvascular ECs (HMVEC-L). Gene expression was measured by RT-qPCR and Western blotting. Cell signaling pathway activation was analyzed by detecting phosphor-ERK and phosphor-AKT levels. Cell migration and apoptosis were assessed using the Boyden chamber assay and the CCK-8 Kit, respectively. Loss of ENG in HUVECs led to significantly reduced expression of VEGFR2 but not TIE2 or FGFR1, which was also confirmed in HMVEC-L. HUVECs lacking ENG had significantly lower levels of active Rac1 and a substantial reduction of the transcription factor Sp1, an activator of VEGFR2 transcription, in nuclei. Furthermore, VEGF- but not bFGF- or angiopoietin-1-induced phosphor-ERK and phosphor-AKT were suppressed in ENG deficient HUVECs. Functional analysis revealed that ENG knockdown inhibited cell migratory but enhanced anti-apoptotic activity induced by VEGF. In contrast, bFGF, angiopoietin-1 and -2 induced HUVEC migration and anti-apoptotic activities were not affected by ENG knockdown. In conclusion, ENG deficiency alters the VEGF/VEGFR2 pathway, which may play a role in HHT pathogenesis.
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Pérez-Rodríguez S, Huang SA, Borau C, García-Aznar JM, Polacheck WJ. Microfluidic model of monocyte extravasation reveals the role of hemodynamics and subendothelial matrix mechanics in regulating endothelial integrity. BIOMICROFLUIDICS 2021; 15:054102. [PMID: 34548891 PMCID: PMC8443302 DOI: 10.1063/5.0061997] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/01/2021] [Accepted: 08/26/2021] [Indexed: 05/08/2023]
Abstract
Extravasation of circulating cells is an essential process that governs tissue inflammation and the body's response to pathogenic infection. To initiate anti-inflammatory and phagocytic functions within tissues, immune cells must cross the vascular endothelial barrier from the vessel lumen to the subluminal extracellular matrix. In this work, we present a microfluidic approach that enables the recreation of a three-dimensional, perfused endothelial vessel formed by human endothelial cells embedded within a collagen-rich matrix. Monocytes are introduced into the vessel perfusate, and we investigate the role of luminal flow and collagen concentration on extravasation. In vessels conditioned with the flow, increased monocyte adhesion to the vascular wall was observed, though fewer monocytes extravasated to the collagen hydrogel. Our results suggest that the lower rates of extravasation are due to the increased vessel integrity and reduced permeability of the endothelial monolayer. We further demonstrate that vascular permeability is a function of collagen hydrogel mass concentration, with increased collagen concentrations leading to elevated vascular permeability and increased extravasation. Collectively, our results demonstrate that extravasation of monocytes is highly regulated by the structural integrity of the endothelial monolayer. The microfluidic approach developed here allows for the dissection of the relative contributions of these cues to further understand the key governing processes that regulate circulating cell extravasation and inflammation.
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Affiliation(s)
| | - Stephanie A. Huang
- Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill and North Carolina State University, Chapel Hill, North Carolina 27599, USA
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Arts JJG, Mahlandt EK, Grönloh MLB, Schimmel L, Noordstra I, Gordon E, van Steen ACI, Tol S, Walzog B, van Rijssel J, Nolte MA, Postma M, Khuon S, Heddleston JM, Wait E, Chew TL, Winter M, Montanez E, Goedhart J, van Buul JD. Endothelial junctional membrane protrusions serve as hotspots for neutrophil transmigration. eLife 2021; 10:66074. [PMID: 34431475 PMCID: PMC8437435 DOI: 10.7554/elife.66074] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2020] [Accepted: 08/22/2021] [Indexed: 12/27/2022] Open
Abstract
Upon inflammation, leukocytes rapidly transmigrate across the endothelium to enter the inflamed tissue. Evidence accumulates that leukocytes use preferred exit sites, alhough it is not yet clear how these hotspots in the endothelium are defined and how they are recognized by the leukocyte. Using lattice light sheet microscopy, we discovered that leukocytes prefer endothelial membrane protrusions at cell junctions for transmigration. Phenotypically, these junctional membrane protrusions are present in an asymmetric manner, meaning that one endothelial cell shows the protrusion and the adjacent one does not. Consequently, leukocytes cross the junction by migrating underneath the protruding endothelial cell. These protrusions depend on Rac1 activity and by using a photo-activatable Rac1 probe, we could artificially generate local exit-sites for leukocytes. Overall, we have discovered a new mechanism that uses local induced junctional membrane protrusions to facilitate/steer the leukocyte escape/exit from inflamed vessel walls.
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Affiliation(s)
- Janine JG Arts
- Molecular Cell Biology Lab at Dept. Molecular Hematology, Sanquin Research and Landsteiner LaboratoryAmsterdamNetherlands
- Leeuwenhoek Centre for Advanced Microscopy (LCAM), section Molecular Cytology at Swammerdam Institute for Life Sciences (SILS) at University of AmsterdamAmsterdamNetherlands
| | - Eike K Mahlandt
- Leeuwenhoek Centre for Advanced Microscopy (LCAM), section Molecular Cytology at Swammerdam Institute for Life Sciences (SILS) at University of AmsterdamAmsterdamNetherlands
| | - Max LB Grönloh
- Molecular Cell Biology Lab at Dept. Molecular Hematology, Sanquin Research and Landsteiner LaboratoryAmsterdamNetherlands
- Leeuwenhoek Centre for Advanced Microscopy (LCAM), section Molecular Cytology at Swammerdam Institute for Life Sciences (SILS) at University of AmsterdamAmsterdamNetherlands
| | - Lilian Schimmel
- Molecular Cell Biology Lab at Dept. Molecular Hematology, Sanquin Research and Landsteiner LaboratoryAmsterdamNetherlands
- Leeuwenhoek Centre for Advanced Microscopy (LCAM), section Molecular Cytology at Swammerdam Institute for Life Sciences (SILS) at University of AmsterdamAmsterdamNetherlands
- Division of Cell and Developmental Biology, Institute for Molecular Bioscience, The University of QueenslandBrisbaneQLDAustralia
| | - Ivar Noordstra
- Division of Cell and Developmental Biology, Institute for Molecular Bioscience, The University of QueenslandBrisbaneQLDAustralia
| | - Emma Gordon
- Division of Cell and Developmental Biology, Institute for Molecular Bioscience, The University of QueenslandBrisbaneQLDAustralia
| | - Abraham CI van Steen
- Molecular Cell Biology Lab at Dept. Molecular Hematology, Sanquin Research and Landsteiner LaboratoryAmsterdamNetherlands
| | - Simon Tol
- Molecular Cell Biology Lab at Dept. Molecular Hematology, Sanquin Research and Landsteiner LaboratoryAmsterdamNetherlands
| | - Barbara Walzog
- Department of Cardiovascular Physiology and Pathophysiology, Walter Brendel Center of Experimental Medicine, Biomedical Center, Ludwig-Maximilians-Universität MünchenPlanegg-MartinsriedGermany
| | - Jos van Rijssel
- Molecular Cell Biology Lab at Dept. Molecular Hematology, Sanquin Research and Landsteiner LaboratoryAmsterdamNetherlands
| | - Martijn A Nolte
- Molecular Cell Biology Lab at Dept. Molecular Hematology, Sanquin Research and Landsteiner LaboratoryAmsterdamNetherlands
| | - Marten Postma
- Leeuwenhoek Centre for Advanced Microscopy (LCAM), section Molecular Cytology at Swammerdam Institute for Life Sciences (SILS) at University of AmsterdamAmsterdamNetherlands
| | - Satya Khuon
- Advanced Imaging Center at Janelia Research Campus, Howard Hughes Medical InstituteAshburnUnited States
| | - John M Heddleston
- Advanced Imaging Center at Janelia Research Campus, Howard Hughes Medical InstituteAshburnUnited States
- Microscopy Facility at the Cleveland Clinic Florida Research and Innovation CenterPort St. LucieUnited States
| | - Eric Wait
- Advanced Imaging Center at Janelia Research Campus, Howard Hughes Medical InstituteAshburnUnited States
| | - Teng Leong Chew
- Advanced Imaging Center at Janelia Research Campus, Howard Hughes Medical InstituteAshburnUnited States
| | - Mark Winter
- Zuckerman Postdoctoral Fellow, Department of Marine Sciences, University of HaifaHaifaIsrael
| | - Eloi Montanez
- Department of Physiological Sciences, Faculty of Medicine and Health Sciences, University of BarcelonaBarcelonaSpain
| | - Joachim Goedhart
- Leeuwenhoek Centre for Advanced Microscopy (LCAM), section Molecular Cytology at Swammerdam Institute for Life Sciences (SILS) at University of AmsterdamAmsterdamNetherlands
| | - Jaap D van Buul
- Molecular Cell Biology Lab at Dept. Molecular Hematology, Sanquin Research and Landsteiner LaboratoryAmsterdamNetherlands
- Leeuwenhoek Centre for Advanced Microscopy (LCAM), section Molecular Cytology at Swammerdam Institute for Life Sciences (SILS) at University of AmsterdamAmsterdamNetherlands
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Zhao P, Yao Q, Zhang PJ, The E, Zhai Y, Ao L, Jarrett MJ, Dinarello CA, Fullerton DA, Meng X. Single-cell RNA-seq reveals a critical role of novel pro-inflammatory EndMT in mediating adverse remodeling in coronary artery-on-a-chip. SCIENCE ADVANCES 2021; 7:eabg1694. [PMID: 34417174 PMCID: PMC8378826 DOI: 10.1126/sciadv.abg1694] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/16/2020] [Accepted: 06/30/2021] [Indexed: 05/09/2023]
Abstract
A three-dimensional microengineered human coronary artery-on-a-chip was developed for investigation of the mechanism by which low and oscillatory shear stress (OSS) induces pro-atherogenic changes. Single-cell RNA sequencing revealed that OSS induced distinct changes in endothelial cells (ECs) including pro-inflammatory endothelial-to-mesenchymal transition (EndMT). OSS promoted pro-inflammatory EndMT through the Notch1/p38 MAPK-NF-κB signaling axis. Moreover, OSS-induced EC phenotypic changes resulted in proliferation and extracellular matrix (ECM) protein up-regulation in smooth muscle cells (SMCs) through the RANTES-mediated paracrine mechanism. IL-37 suppressed OSS-induced pro-inflammatory EndMT and thereby abrogated SMC proliferation and ECM protein remodeling. Overall, this study provides insights into endothelial heterogeneity under atheroprone shear stress and identifies the mechanistic role of a novel EC subtype in promoting adverse vascular remodeling. Further, this study demonstrates that anti-inflammatory approach is capable of mitigating vascular pathobiology evoked by atheroprone shear stress.
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Affiliation(s)
- Peng Zhao
- Department of Surgery, University of Colorado Denver, Aurora, CO, USA
| | - Qingzhou Yao
- Department of Surgery, University of Colorado Denver, Aurora, CO, USA
| | - Pei-Jian Zhang
- Department of Surgery, University of Colorado Denver, Aurora, CO, USA
| | - Erlinda The
- Department of Surgery, University of Colorado Denver, Aurora, CO, USA
| | - Yufeng Zhai
- Department of Surgery, University of Colorado Denver, Aurora, CO, USA
| | - Lihua Ao
- Department of Surgery, University of Colorado Denver, Aurora, CO, USA
| | - Michael J Jarrett
- Department of Surgery, University of Colorado Denver, Aurora, CO, USA
| | | | - David A Fullerton
- Department of Surgery, University of Colorado Denver, Aurora, CO, USA
| | - Xianzhong Meng
- Department of Surgery, University of Colorado Denver, Aurora, CO, USA.
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Huang Y, Qian JY, Cheng H, Li XM. Effects of shear stress on differentiation of stem cells into endothelial cells. World J Stem Cells 2021; 13:894-913. [PMID: 34367483 PMCID: PMC8316872 DOI: 10.4252/wjsc.v13.i7.894] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2021] [Revised: 04/20/2021] [Accepted: 06/22/2021] [Indexed: 02/06/2023] Open
Abstract
Stem cell transplantation is an appealing potential therapy for vascular diseases and an indispensable key step in vascular tissue engineering. Substantial effort has been made to differentiate stem cells toward vascular cell phenotypes, including endothelial cells (ECs) and smooth muscle cells. The microenvironment of vascular cells not only contains biochemical factors that influence differentiation but also exerts hemodynamic forces, such as shear stress and cyclic strain. More recently, studies have shown that shear stress can influence the differentiation of stem cells toward ECs. A deep understanding of the responses and underlying mechanisms involved in this process is essential for clinical translation. This review highlights current data supporting the role of shear stress in stem cell differentiation into ECs. Potential mechanisms and signaling cascades for transducing shear stress into a biological signal are proposed. Further study of stem cell responses to shear stress will be necessary to apply stem cells for pharmacological applications and cardiovascular implants in the realm of regenerative medicine.
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Affiliation(s)
- Yan Huang
- Key Laboratory for Biomechanics and Mechanobiology of Ministry of Education, Beijing Advanced Innovation Center for Biomedical Engineering, School of Biological Science and Medical Engineering, Beihang University, Beijing 100083, China
| | - Jia-Yi Qian
- Key Laboratory for Biomechanics and Mechanobiology of Ministry of Education, Beijing Advanced Innovation Center for Biomedical Engineering, School of Biological Science and Medical Engineering, Beihang University, Beijing 100083, China
| | - Hong Cheng
- Key Laboratory for Biomechanics and Mechanobiology of Ministry of Education, Beijing Advanced Innovation Center for Biomedical Engineering, School of Biological Science and Medical Engineering, Beihang University, Beijing 100083, China
| | - Xiao-Ming Li
- Key Laboratory for Biomechanics and Mechanobiology of Ministry of Education, Beijing Advanced Innovation Center for Biomedical Engineering, School of Biological Science and Medical Engineering, Beihang University, Beijing 100083, China.
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35
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Okamoto T, Park EJ, Kawamoto E, Usuda H, Wada K, Taguchi A, Shimaoka M. Endothelial connexin-integrin crosstalk in vascular inflammation. Biochim Biophys Acta Mol Basis Dis 2021; 1867:166168. [PMID: 33991620 DOI: 10.1016/j.bbadis.2021.166168] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Revised: 04/18/2021] [Accepted: 05/02/2021] [Indexed: 02/06/2023]
Abstract
Cardiovascular diseases including blood vessel disorders represent a major cause of death globally. The essential roles played by local and systemic vascular inflammation in the pathogenesis of cardiovascular diseases have been increasingly recognized. Vascular inflammation triggers the aberrant activation of endothelial cells, which leads to the functional and structural abnormalities in vascular vessels. In addition to humoral mediators such as pro-inflammatory cytokines and prostaglandins, the alteration of physical and mechanical microenvironment - including vascular stiffness and shear stress - modify the gene expression profiles and metabolic profiles of endothelial cells via mechano-transduction pathways, thereby contributing to the pathogenesis of vessel disorders. Notably, connexins and integrins crosstalk each other in response to the mechanical stress, and, thereby, play an important role in regulating the mechano-transduction of endothelial cells. Here, we provide an overview on how the inter-play between connexins and integrins in endothelial cells unfold during the mechano-transduction in vascular inflammation.
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Affiliation(s)
- Takayuki Okamoto
- Department of Pharmacology, Faculty of Medicine, Shimane University, 89-1 Enya-cho, Izumo-city, Shimane 693-8501, Japan.
| | - Eun Jeong Park
- Department of Molecular Pathobiology and Cell Adhesion Biology, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu-city, Mie 514-8507, Japan
| | - Eiji Kawamoto
- Department of Molecular Pathobiology and Cell Adhesion Biology, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu-city, Mie 514-8507, Japan; Department of Emergency and Disaster Medicine, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu-city, Mie 514-8507, Japan
| | - Haruki Usuda
- Department of Pharmacology, Faculty of Medicine, Shimane University, 89-1 Enya-cho, Izumo-city, Shimane 693-8501, Japan
| | - Koichiro Wada
- Department of Pharmacology, Faculty of Medicine, Shimane University, 89-1 Enya-cho, Izumo-city, Shimane 693-8501, Japan
| | - Akihiko Taguchi
- Department of Regenerative Medicine Research, Foundation for Biomedical Research and Innovation at Kobe, 2-2 Minatojima-Minamimachi, Chuo-ku, Kobe 650-0047, Japan
| | - Motomu Shimaoka
- Department of Molecular Pathobiology and Cell Adhesion Biology, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu-city, Mie 514-8507, Japan.
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36
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Fiani B, Fowler JB, Figueras RA, Hessamian K, Mercado N, Vukcevich O, Singh MK. Ruptured cerebral aneurysms in COVID-19 patients: A review of literature with case examples. Surg Neurol Int 2021; 12:187. [PMID: 34084615 PMCID: PMC8168707 DOI: 10.25259/sni_214_2021] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2021] [Accepted: 04/02/2021] [Indexed: 12/19/2022] Open
Abstract
Background The novel severe acute respiratory syndrome coronavirus 2 is responsible for over 83 million cases of infection and over 1.8 million deaths since the emergence of the COVID-19 pandemic. Because COVID-19 infection is associated with a devastating mortality rate and myriad complications, it is critical that clinicians better understand its pathophysiology to develop effective treatment. Cumulative evidence is suggestive of cerebral aneurysms being intertwined with the hyperinflammatory state and hypercytokinemia observed in severe COVID-19 infections. Case Description In case example 1, the patient presents with chills, a mild cough, and sore throat. The patient develops high-grade fever of 39.8° C, decreased oxygen saturation of 93% on room air, and an extensive spontaneous subarachnoid hemorrhage (SAH) in the basal cisterns from a ruptured left posterior communicating artery aneurysm. In case example 2, the patient presents with a positive PCR test for COVID-19 2 weeks prior with spontaneous SAH and found to have a large multilobulated bulbous ruptured aneurysm of the anterior communicating artery. Both patients' symptoms and high-grade fever are consistent with hypercytokinemia and a hyperinflammatory state, with elevated granulocyte colony-stimulating factor, inducible protein-10, monocyte chemoattractant protein-1, M1P1A, and tumor necrosis factor-α inflammatory mediators found to be elevated in COVID-19 intensive care unit admissions. Conclusion COVID-19 effect on cerebral aneurysms requires future studies to clearly delineate correlation, however, hypercytokinemia and a hyperinflammatory state are strongly implicated to cause degenerative vascular changes that may predispose patients to cerebral aneurysm formation, change in size or morphology, and resultant aneurysm rupture.
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Affiliation(s)
- Brian Fiani
- Department of Neurosurgery, Desert Regional Medical Center, Palm Springs, United States
| | - James B Fowler
- Department of Neurosurgery, Desert Regional Medical Center, Palm Springs, United States
| | - Ryan Arthur Figueras
- School of Medicine, University of California Riverside, Riverside, California, United States
| | - Keon Hessamian
- School of Medicine, University of California Riverside, Riverside, California, United States
| | - Nathan Mercado
- School of Medicine, University of California Riverside, Riverside, California, United States
| | - Olivia Vukcevich
- School of Medicine, University of California Riverside, Riverside, California, United States
| | - Manpreet Kaur Singh
- School of Medicine, University of California Riverside, Riverside, California, United States
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37
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Evers TMJ, Holt LJ, Alberti S, Mashaghi A. Reciprocal regulation of cellular mechanics and metabolism. Nat Metab 2021; 3:456-468. [PMID: 33875882 PMCID: PMC8863344 DOI: 10.1038/s42255-021-00384-w] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/24/2020] [Accepted: 03/12/2021] [Indexed: 12/12/2022]
Abstract
Metabolism and mechanics are intrinsically intertwined. External forces, sensed through the cytoskeleton or distortion of the cell and organelles, induce metabolic changes in the cell. The resulting changes in metabolism, in turn, feed back to regulate every level of cell biology, including the mechanical properties of cells and tissues. Here we examine the links between metabolism and mechanics, highlighting signalling pathways involved in the regulation and response to cellular mechanosensing. We consider how forces and metabolism regulate one another through nanoscale molecular sensors, micrometre-scale cytoskeletal networks, organelles and dynamic biomolecular condensates. Understanding this cross-talk will create diagnostic and therapeutic opportunities for metabolic disorders such as cancer, cardiovascular pathologies and obesity.
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Affiliation(s)
- Tom M J Evers
- Medical Systems Biophysics and Bioengineering, Leiden Academic Centre for Drug Research, Faculty of Science, Leiden University, Leiden, the Netherlands
| | - Liam J Holt
- Institute for Systems Genetics, New York University Langone Health, New York, NY, USA
| | - Simon Alberti
- Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany
| | - Alireza Mashaghi
- Medical Systems Biophysics and Bioengineering, Leiden Academic Centre for Drug Research, Faculty of Science, Leiden University, Leiden, the Netherlands.
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38
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Tanaka K, Joshi D, Timalsina S, Schwartz MA. Early events in endothelial flow sensing. Cytoskeleton (Hoboken) 2021; 78:217-231. [PMID: 33543538 DOI: 10.1002/cm.21652] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2020] [Revised: 01/29/2021] [Accepted: 01/31/2021] [Indexed: 12/15/2022]
Abstract
Responses of vascular and lymphatic endothelial cells (ECs) to fluid shear stress (FSS) from blood or lymphatic fluid flow govern the development, physiology, and diseases of these structures. Extensive research has characterized the signaling, gene expression and cytoskeletal pathways that mediate effects on EC phenotype and vascular morphogenesis. But the primary mechanisms by which ECs transduce the weak forces from flow into biochemical signals are less well understood. This review covers recent advances in our understanding of the immediate mechanisms of FSS mechanotransduction, integrating results from different disciplines, addressing their roles in development, physiology and disease, and suggesting important questions for future work.
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Affiliation(s)
- Keiichiro Tanaka
- Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, School of Medicine, Yale University, New Haven, Connecticut, USA
| | - Divyesh Joshi
- Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, School of Medicine, Yale University, New Haven, Connecticut, USA
| | - Sushma Timalsina
- Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, School of Medicine, Yale University, New Haven, Connecticut, USA
| | - Martin A Schwartz
- Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, School of Medicine, Yale University, New Haven, Connecticut, USA.,Department of Cell Biology, Yale University, New Haven, Connecticut, USA.,Department of Biomedical engineering, Yale University, New Haven, Connecticut, USA
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Ayuzawa N, Fujita T. The Mineralocorticoid Receptor in Salt-Sensitive Hypertension and Renal Injury. J Am Soc Nephrol 2021; 32:279-289. [PMID: 33397690 PMCID: PMC8054893 DOI: 10.1681/asn.2020071041] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
Hypertension and its comorbidities pose a major public health problem associated with disease-associated factors related to a modern lifestyle, such high salt intake or obesity. Accumulating evidence has demonstrated that aldosterone and its receptor, the mineralocorticoid receptor (MR), have crucial roles in the development of salt-sensitive hypertension and coexisting cardiovascular and renal injuries. Accordingly, clinical trials have repetitively shown the promising effects of MR blockers in these diseases. We and other researchers have identified novel mechanisms of MR activation involved in salt-sensitive hypertension and renal injury, including the obesity-derived overproduction of aldosterone and ligand-independent signaling. Moreover, recent advances in the analysis of cell-specific and context-dependent mechanisms of MR activation in various tissues-including a classic target of aldosterone, aldosterone-sensitive distal nephrons-are now providing new insights. In this review, we summarize recent updates to our understanding of aldosterone-MR signaling, focusing on its role in salt-sensitive hypertension and renal injury.
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Affiliation(s)
- Nobuhiro Ayuzawa
- Division of Clinical Epigenetics, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan
| | - Toshiro Fujita
- Division of Clinical Epigenetics, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan,Shinshu University School of Medicine, Nagano, Japan,Research Center for Social Systems, Shinshu University, Nagano, Japan
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40
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Driscoll TP, Ahn SJ, Huang B, Kumar A, Schwartz MA. Actin flow-dependent and -independent force transmission through integrins. Proc Natl Acad Sci U S A 2020; 117:32413-32422. [PMID: 33262280 PMCID: PMC7768777 DOI: 10.1073/pnas.2010292117] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023] Open
Abstract
Integrin-dependent adhesions mediate reciprocal exchange of force and information between the cell and the extracellular matrix. These effects are attributed to the "focal adhesion clutch," in which moving actin filaments transmit force to integrins via dynamic protein interactions. To elucidate these processes, we measured force on talin together with actin flow speed. While force on talin in small lamellipodial adhesions correlated with actin flow, talin tension in large adhesions further from the cell edge was mainly flow-independent. Stiff substrates shifted force transfer toward the flow-independent mechanism. Flow-dependent force transfer required talin's C-terminal actin binding site, ABS3, but not vinculin. Flow-independent force transfer initially required vinculin and at later times the central actin binding site, ABS2. Force transfer through integrins thus occurs not through a continuous clutch but through a series of discrete states mediated by distinct protein interactions, with their ratio modulated by substrate stiffness.
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Affiliation(s)
- Tristan P Driscoll
- Yale Cardiovascular Research Center, Department of Internal Medicine, Section of Cardiovascular Medicine, Yale University, New Haven, CT 06511
- Department of Chemical and Biomedical Engineering, Florida A&M University-Florida State University College of Engineering, Tallahassee, FL 32310
| | - Sang Joon Ahn
- Yale Cardiovascular Research Center, Department of Internal Medicine, Section of Cardiovascular Medicine, Yale University, New Haven, CT 06511
| | - Billy Huang
- Yale Cardiovascular Research Center, Department of Internal Medicine, Section of Cardiovascular Medicine, Yale University, New Haven, CT 06511
| | - Abhishek Kumar
- Yale Cardiovascular Research Center, Department of Internal Medicine, Section of Cardiovascular Medicine, Yale University, New Haven, CT 06511
| | - Martin A Schwartz
- Yale Cardiovascular Research Center, Department of Internal Medicine, Section of Cardiovascular Medicine, Yale University, New Haven, CT 06511;
- Department of Cell Biology, Yale University, New Haven, CT 06511
- Department of Biomedical Engineering, School of Engineering and Applied Science, Yale University, New Haven, CT 06511
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41
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Nakayama A, Albarrán-Juárez J, Liang G, Roquid KA, Iring A, Tonack S, Chen M, Müller OJ, Weinstein LS, Offermanns S. Disturbed flow-induced Gs-mediated signaling protects against endothelial inflammation and atherosclerosis. JCI Insight 2020; 5:140485. [PMID: 33268595 PMCID: PMC7714404 DOI: 10.1172/jci.insight.140485] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2020] [Accepted: 10/28/2020] [Indexed: 01/05/2023] Open
Abstract
Atherosclerosis develops preferentially in areas of the arterial system, in which blood flow is disturbed. Exposure of endothelial cells to disturbed flow has been shown to induce inflammatory signaling, including NF-κB activation, which leads to the expression of leukocyte adhesion molecules and chemokines. Here, we show that disturbed flow promotes the release of adrenomedullin from endothelial cells, which in turn activates its Gs-coupled receptor calcitonin receptor–like receptor (CALCRL). This induces antiinflammatory signaling through cAMP and PKA, and it results in reduced endothelial inflammation in vitro and in vivo. Suppression of endothelial expression of Gαs, the α subunit of the G-protein Gs; CALCRL; or adrenomedullin leads to increased disturbed flow–induced inflammatory signaling in vitro and in vivo. Furthermore, mice with induced endothelial-specific deficiency of Gαs, CALCRL, or adrenomedullin show increased atherosclerotic lesions. Our data identify an antiinflammatory signaling pathway in endothelial cells stimulated by disturbed flow and suggest activation of the endothelial adrenomedullin/CALCRL/Gs system as a promising approach to inhibit progression of atherosclerosis. Disturbed flow promotes the release of adrenomedullin from endothelial cells and activates Gs-mediated signaling, which reduces endothelial inflammation in vitro and in vivo.
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Affiliation(s)
- Akiko Nakayama
- Max Planck Institute for Heart and Lung Research, Department of Pharmacology, Bad Nauheim, Germany
| | - Julián Albarrán-Juárez
- Max Planck Institute for Heart and Lung Research, Department of Pharmacology, Bad Nauheim, Germany
| | - Guozheng Liang
- Max Planck Institute for Heart and Lung Research, Department of Pharmacology, Bad Nauheim, Germany
| | - Kenneth Anthony Roquid
- Max Planck Institute for Heart and Lung Research, Department of Pharmacology, Bad Nauheim, Germany
| | - András Iring
- Max Planck Institute for Heart and Lung Research, Department of Pharmacology, Bad Nauheim, Germany
| | - Sarah Tonack
- Max Planck Institute for Heart and Lung Research, Department of Pharmacology, Bad Nauheim, Germany
| | - Min Chen
- Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland, USA
| | - Oliver J Müller
- Department of Internal Medicine III, University of Kiel, Kiel, and German Center for Cardiovascular Research (DZHK), Partner site Hamburg/Kiel/Lübeck, Germany
| | - Lee S Weinstein
- Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland, USA
| | - Stefan Offermanns
- Max Planck Institute for Heart and Lung Research, Department of Pharmacology, Bad Nauheim, Germany.,Centre for Molecular Medicine, Medical Faculty, J.W. Goethe University Frankfurt, Frankfurt, Germany.,DZHK RheinMain, Germany
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42
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Reina-Torres E, De Ieso ML, Pasquale LR, Madekurozwa M, van Batenburg-Sherwood J, Overby DR, Stamer WD. The vital role for nitric oxide in intraocular pressure homeostasis. Prog Retin Eye Res 2020; 83:100922. [PMID: 33253900 DOI: 10.1016/j.preteyeres.2020.100922] [Citation(s) in RCA: 54] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2020] [Revised: 11/13/2020] [Accepted: 11/23/2020] [Indexed: 02/07/2023]
Abstract
Catalyzed by endothelial nitric oxide (NO) synthase (eNOS) activity, NO is a gaseous signaling molecule maintaining endothelial and cardiovascular homeostasis. Principally, NO regulates the contractility of vascular smooth muscle cells and permeability of endothelial cells in response to either biochemical or biomechanical cues. In the conventional outflow pathway of the eye, the smooth muscle-like trabecular meshwork (TM) cells and Schlemm's canal (SC) endothelium control aqueous humor outflow resistance, and therefore intraocular pressure (IOP). The mechanisms by which outflow resistance is regulated are complicated, but NO appears to be a key player as enhancement or inhibition of NO signaling dramatically affects outflow function; and polymorphisms in NOS3, the gene that encodes eNOS modifies the relation between various environmental exposures and glaucoma. Based upon a comprehensive review of past foundational studies, we present a model whereby NO controls a feedback signaling loop in the conventional outflow pathway that is sensitive to changes in IOP and its oscillations. Thus, upon IOP elevation, the outflow pathway tissues distend, and the SC lumen narrows resulting in increased SC endothelial shear stress and stretch. In response, SC cells upregulate the production of NO, relaxing neighboring TM cells and increasing permeability of SC's inner wall. These IOP-dependent changes in the outflow pathway tissues reduce the resistance to aqueous humor drainage and lower IOP, which, in turn, diminishes the biomechanical signaling on SC. Similar to cardiovascular pathogenesis, dysregulation of the eNOS/NO system leads to dysfunctional outflow regulation and ocular hypertension, eventually resulting in primary open-angle glaucoma.
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Affiliation(s)
| | | | - Louis R Pasquale
- Eye and Vision Research Institute of New York Eye and Ear Infirmary at Mount Sinai, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | | | | | - Darryl R Overby
- Department of Bioengineering, Imperial College London, London, UK.
| | - W Daniel Stamer
- Department of Ophthalmology, Duke University, Durham, NC, USA.
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Bajpai A, Li R, Chen W. The cellular mechanobiology of aging: from biology to mechanics. Ann N Y Acad Sci 2020; 1491:3-24. [PMID: 33231326 DOI: 10.1111/nyas.14529] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2020] [Revised: 10/10/2020] [Accepted: 10/21/2020] [Indexed: 12/14/2022]
Abstract
Aging is a chronic, complicated process that leads to degenerative physical and biological changes in living organisms. Aging is associated with permanent, gradual physiological cellular decay that affects all aspects of cellular mechanobiological features, including cellular cytoskeleton structures, mechanosensitive signaling pathways, and forces in the cell, as well as the cell's ability to sense and adapt to extracellular biomechanical signals in the tissue environment through mechanotransduction. These mechanobiological changes in cells are directly or indirectly responsible for dysfunctions and diseases in various organ systems, including the cardiovascular, musculoskeletal, skin, and immune systems. This review critically examines the role of aging in the progressive decline of the mechanobiology occurring in cells, and establishes mechanistic frameworks to understand the mechanobiological effects of aging on disease progression and to develop new strategies for halting and reversing the aging process. Our review also highlights the recent development of novel bioengineering approaches for studying the key mechanobiological mechanisms in aging.
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Affiliation(s)
- Apratim Bajpai
- Department of Mechanical and Aerospace Engineering, Tandon School of Engineering, New York University, Brooklyn, New York
| | - Rui Li
- Department of Mechanical and Aerospace Engineering, Tandon School of Engineering, New York University, Brooklyn, New York.,Department of Biomedical Engineering, Tandon School of Engineering, New York University, Brooklyn, New York
| | - Weiqiang Chen
- Department of Mechanical and Aerospace Engineering, Tandon School of Engineering, New York University, Brooklyn, New York.,Department of Biomedical Engineering, Tandon School of Engineering, New York University, Brooklyn, New York.,Laura and Isaac Perlmutter Cancer Center, NYU Langone Health, New York, New York
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Bovée DM, Cuevas CA, Zietse R, Danser AHJ, Mirabito Colafella KM, Hoorn EJ. Salt-sensitive hypertension in chronic kidney disease: distal tubular mechanisms. Am J Physiol Renal Physiol 2020; 319:F729-F745. [DOI: 10.1152/ajprenal.00407.2020] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Chronic kidney disease (CKD) causes salt-sensitive hypertension that is often resistant to treatment and contributes to the progression of kidney injury and cardiovascular disease. A better understanding of the mechanisms contributing to salt-sensitive hypertension in CKD is essential to improve these outcomes. This review critically explores these mechanisms by focusing on how CKD affects distal nephron Na+ reabsorption. CKD causes glomerulotubular imbalance with reduced proximal Na+ reabsorption and increased distal Na+ delivery and reabsorption. Aldosterone secretion further contributes to distal Na+ reabsorption in CKD and is not only mediated by renin and K+ but also by metabolic acidosis, endothelin-1, and vasopressin. CKD also activates the intrarenal renin-angiotensin system, generating intratubular angiotensin II to promote distal Na+ reabsorption. High dietary Na+ intake in CKD contributes to Na+ retention by aldosterone-independent activation of the mineralocorticoid receptor mediated through Rac1. High dietary Na+ also produces an inflammatory response mediated by T helper 17 cells and cytokines increasing distal Na+ transport. CKD is often accompanied by proteinuria, which contains plasmin capable of activating the epithelial Na+ channel. Thus, CKD causes both local and systemic changes that together promote distal nephron Na+ reabsorption and salt-sensitive hypertension. Future studies should address remaining knowledge gaps, including the relative contribution of each mechanism, the influence of sex, differences between stages and etiologies of CKD, and the clinical relevance of experimentally identified mechanisms. Several pathways offer opportunities for intervention, including with dietary Na+ reduction, distal diuretics, renin-angiotensin system inhibitors, mineralocorticoid receptor antagonists, and K+ or H+ binders.
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Affiliation(s)
- Dominique M. Bovée
- Division of Nephrology and Transplantation, Department of Internal Medicine, Erasmus MC, Erasmus University Medical Center, Rotterdam, The Netherlands
- Division of Vascular Medicine, Department of Internal Medicine, Erasmus MC, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Catharina A. Cuevas
- Division of Nephrology and Transplantation, Department of Internal Medicine, Erasmus MC, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Robert Zietse
- Division of Nephrology and Transplantation, Department of Internal Medicine, Erasmus MC, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - A. H. Jan Danser
- Division of Vascular Medicine, Department of Internal Medicine, Erasmus MC, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Katrina M. Mirabito Colafella
- Cardiovascular Disease Program, Monash Biomedicine Discovery Institute, Monash University, Melbourne, Victoria, Australia
- Department of Physiology, Monash University, Melbourne, Victoria, Australia
| | - Ewout J. Hoorn
- Division of Nephrology and Transplantation, Department of Internal Medicine, Erasmus MC, Erasmus University Medical Center, Rotterdam, The Netherlands
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Buwa N, Mazumdar D, Balasubramanian N. Caveolin1 Tyrosine-14 Phosphorylation: Role in Cellular Responsiveness to Mechanical Cues. J Membr Biol 2020; 253:509-534. [PMID: 33089394 DOI: 10.1007/s00232-020-00143-0] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2020] [Accepted: 10/05/2020] [Indexed: 02/07/2023]
Abstract
The plasma membrane is a dynamic lipid bilayer that engages with the extracellular microenvironment and intracellular cytoskeleton. Caveolae are distinct plasma membrane invaginations lined by integral membrane proteins Caveolin1, 2, and 3. Caveolae formation and stability is further supported by additional proteins including Cavin1, EHD2, Pacsin2 and ROR1. The lipid composition of caveolar membranes, rich in cholesterol and phosphatidylserine, actively contributes to caveolae formation and function. Post-translational modifications of Cav1, including its phosphorylation of the tyrosine-14 residue (pY14Cav1) are vital to its function in and out of caveolae. Cells that experience significant mechanical stress are seen to have abundant caveolae. They play a vital role in regulating cellular signaling and endocytosis, which could further affect the abundance and distribution of caveolae at the PM, contributing to sensing and/or buffering mechanical stress. Changes in membrane tension in cells responding to multiple mechanical stimuli affects the organization and function of caveolae. These mechanical cues regulate pY14Cav1 levels and function in caveolae and focal adhesions. This review, along with looking at the mechanosensitive nature of caveolae, focuses on the role of pY14Cav1 in regulating cellular mechanotransduction.
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Affiliation(s)
- Natasha Buwa
- Indian Institute of Science Education and Research, Pune, Dr. Homi Bhabha Road, Pashan, Pune, 411008, India
| | - Debasmita Mazumdar
- Indian Institute of Science Education and Research, Pune, Dr. Homi Bhabha Road, Pashan, Pune, 411008, India
| | - Nagaraj Balasubramanian
- Indian Institute of Science Education and Research, Pune, Dr. Homi Bhabha Road, Pashan, Pune, 411008, India.
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Jang LK, Alvarado JA, Pepona M, Wasson EM, Nash LD, Ortega JM, Randles A, Maitland DJ, Moya ML, Hynes WF. Three-dimensional bioprinting of aneurysm-bearing tissue structure for endovascular deployment of embolization coils. Biofabrication 2020; 13. [DOI: 10.1088/1758-5090/abbb9b] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2020] [Accepted: 09/25/2020] [Indexed: 01/30/2023]
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Santamaría R, González-Álvarez M, Delgado R, Esteban S, Arroyo AG. Remodeling of the Microvasculature: May the Blood Flow Be With You. Front Physiol 2020; 11:586852. [PMID: 33178049 PMCID: PMC7593767 DOI: 10.3389/fphys.2020.586852] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2020] [Accepted: 09/09/2020] [Indexed: 12/12/2022] Open
Abstract
The vasculature ensures optimal delivery of nutrients and oxygen throughout the body, and to achieve this function it must continually adapt to varying tissue demands. Newly formed vascular plexuses during development are immature and require dynamic remodeling to generate well-patterned functional networks. This is achieved by remodeling of the capillaries preserving those which are functional and eliminating other ones. A balanced and dynamically regulated capillary remodeling will therefore ensure optimal distribution of blood and nutrients to the tissues. This is particularly important in pathological contexts in which deficient or excessive vascular remodeling may worsen tissue perfusion and hamper tissue repair. Blood flow is a major determinant of microvascular reshaping since capillaries are pruned when relatively less perfused and they split when exposed to high flow in order to shape the microvascular network for optimal tissue perfusion and oxygenation. The molecular machinery underlying blood flow sensing by endothelial cells is being deciphered, but much less is known about how this translates into endothelial cell responses as alignment, polarization and directed migration to drive capillary remodeling, particularly in vivo. Part of this knowledge is theoretical from computational models since blood flow hemodynamics are not easily recapitulated by in vitro or ex vivo approaches. Moreover, these events are difficult to visualize in vivo due to their infrequency and briefness. Studies had been limited to postnatal mouse retina and vascular beds in zebrafish but new tools as advanced microscopy and image analysis are strengthening our understanding of capillary remodeling. In this review we introduce the concept of remodeling of the microvasculature and its relevance in physiology and pathology. We summarize the current knowledge on the mechanisms contributing to capillary regression and to capillary splitting highlighting the key role of blood flow to orchestrate these processes. Finally, we comment the potential and possibilities that microfluidics offers to this field. Since capillary remodeling mechanisms are often reactivated in prevalent pathologies as cancer and cardiovascular disease, all this knowledge could be eventually used to improve the functionality of capillary networks in diseased tissues and promote their repair.
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Affiliation(s)
- Ricardo Santamaría
- Department of Vascular Pathophysiology, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain
| | - María González-Álvarez
- Department of Molecular Biomedicine, Centro de Investigaciones Biológicas Margarita Salas (CIB-CSIC), Madrid, Spain
| | - Raquel Delgado
- Department of Vascular Pathophysiology, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain
| | - Sergio Esteban
- Department of Vascular Pathophysiology, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain
| | - Alicia G. Arroyo
- Department of Vascular Pathophysiology, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain
- Department of Molecular Biomedicine, Centro de Investigaciones Biológicas Margarita Salas (CIB-CSIC), Madrid, Spain
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Bosseboeuf E, Raimondi C. Signalling, Metabolic Pathways and Iron Homeostasis in Endothelial Cells in Health, Atherosclerosis and Alzheimer's Disease. Cells 2020; 9:cells9092055. [PMID: 32911833 PMCID: PMC7564205 DOI: 10.3390/cells9092055] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2020] [Revised: 09/04/2020] [Accepted: 09/04/2020] [Indexed: 02/06/2023] Open
Abstract
Endothelial cells drive the formation of new blood vessels in physiological and pathological contexts such as embryonic development, wound healing, cancer and ocular diseases. Once formed, all vessels of the vasculature system present an endothelial monolayer (the endothelium), lining the luminal wall of the vessels, that regulates gas and nutrient exchange between the circulating blood and tissues, contributing to maintaining tissue and vascular homeostasis. To perform their functions, endothelial cells integrate signalling pathways promoted by growth factors, cytokines, extracellular matrix components and signals from mechanosensory complexes sensing the blood flow. New evidence shows that endothelial cells rely on specific metabolic pathways for distinct cellular functions and that the integration of signalling and metabolic pathways regulates endothelial-dependent processes such as angiogenesis and vascular homeostasis. In this review, we provide an overview of endothelial functions and the recent advances in understanding the role of endothelial signalling and metabolism in physiological processes such as angiogenesis and vascular homeostasis and vascular diseases. Also, we focus on the signalling pathways promoted by the transmembrane protein Neuropilin-1 (NRP1) in endothelial cells, its recently discovered role in regulating mitochondrial function and iron homeostasis and the role of mitochondrial dysfunction and iron in atherosclerosis and neurodegenerative diseases.
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Zhang C, Zhou T, Chen Z, Yan M, Li B, Lv H, Wang C, Xiang S, Shi L, Zhu Y, Ai D. Coupling of Integrin α5 to Annexin A2 by Flow Drives Endothelial Activation. Circ Res 2020; 127:1074-1090. [PMID: 32673515 DOI: 10.1161/circresaha.120.316857] [Citation(s) in RCA: 74] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
RATIONALE Atherosclerosis preferentially occurs at specific sites of the vasculature where endothelial cells (ECs) are exposed to disturbed blood flow. Translocation of integrin α5 to lipid rafts promotes integrin activation and ligation, which is critical for oscillatory shear stress (OSS)-induced EC activation. However, the underlying mechanism of OSS promoted integrin α5 lipid raft translocation has remained largely unknown. OBJECTIVE The objective of this study was to specify the mechanotransduction mechanism of OSS-induced integrin α5 translocation and subsequent EC activation. METHODS AND RESULTS Mass spectrometry studies identified endothelial ANXA2 (annexin A2) as a potential carrier allowing integrin α5β1 to traffic in response to OSS. Interference by siRNA of AnxA2 in ECs greatly decreased OSS-induced integrin α5β1 translocation to lipid rafts, EC activation, and monocyte adhesion. Pharmacological and genetic inhibition of PTP1B (protein tyrosine phosphatase 1B) blunted OSS-induced integrin α5β1 activation, which is dependent on Piezo1-mediated calcium influx in ECs. Furthermore, ANXA2 was identified as a direct substrate of activated PTP1B by mass spectrometry. Using bioluminescence resonance energy transfer assay, PTP1B-dephosphorylated ANXA2 at Y24 was found to lead to conformational freedom of the C-terminal core domain from the N-terminal domain of ANXA2. Immunoprecipitation assays showed that this unmasked ANXA2-C-terminal core domain specifically binds to an integrin α5 nonconserved cytoplasmic domain but not β1. Importantly, ectopic lentiviral overexpression of an ANXA2Y24F mutant increased and shRNA against Ptp1B decreased integrin α5β1 ligation, inflammatory signaling, and progression of plaques at atheroprone sites in apolipoprotein E (ApoE)-/- mice. However, the antiatherosclerotic effect of Ptp1B shRNA was abolished in AnxA2-/-ApoE-/- mice. CONCLUSIONS Our data elucidate a novel endothelial mechanotransduction molecular mechanism linking atheroprone flow and activation of integrin α5β1, thereby identifying a class of potential therapeutic targets for atherosclerosis. Graphic Abstract: An graphic abstract is available for this article.
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Affiliation(s)
- Chenghu Zhang
- State Key Laboratory of Experimental Hematology, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education) and Department of Physiology and Pathophysiology, Tianjin Key Laboratory of Metabolic Diseases (C.Z., T.Z., Z.C., M.Y., B.L., H.L., C.W., Y.Z., D.A.), Tianjin Medical University, China
| | - Ting Zhou
- State Key Laboratory of Experimental Hematology, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education) and Department of Physiology and Pathophysiology, Tianjin Key Laboratory of Metabolic Diseases (C.Z., T.Z., Z.C., M.Y., B.L., H.L., C.W., Y.Z., D.A.), Tianjin Medical University, China
| | - Zhipeng Chen
- State Key Laboratory of Experimental Hematology, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education) and Department of Physiology and Pathophysiology, Tianjin Key Laboratory of Metabolic Diseases (C.Z., T.Z., Z.C., M.Y., B.L., H.L., C.W., Y.Z., D.A.), Tianjin Medical University, China
| | - Meng Yan
- State Key Laboratory of Experimental Hematology, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education) and Department of Physiology and Pathophysiology, Tianjin Key Laboratory of Metabolic Diseases (C.Z., T.Z., Z.C., M.Y., B.L., H.L., C.W., Y.Z., D.A.), Tianjin Medical University, China
| | - Bochuan Li
- State Key Laboratory of Experimental Hematology, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education) and Department of Physiology and Pathophysiology, Tianjin Key Laboratory of Metabolic Diseases (C.Z., T.Z., Z.C., M.Y., B.L., H.L., C.W., Y.Z., D.A.), Tianjin Medical University, China
| | - Huizhen Lv
- State Key Laboratory of Experimental Hematology, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education) and Department of Physiology and Pathophysiology, Tianjin Key Laboratory of Metabolic Diseases (C.Z., T.Z., Z.C., M.Y., B.L., H.L., C.W., Y.Z., D.A.), Tianjin Medical University, China.,National Clinical Research Center for Blood Diseases; Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China (H.L., L.S., D.A.)
| | - Chunjiong Wang
- State Key Laboratory of Experimental Hematology, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education) and Department of Physiology and Pathophysiology, Tianjin Key Laboratory of Metabolic Diseases (C.Z., T.Z., Z.C., M.Y., B.L., H.L., C.W., Y.Z., D.A.), Tianjin Medical University, China
| | - Song Xiang
- Department of Biochemistry and Molecular Biology (S.X., L.S.), Tianjin Medical University, China
| | - Lei Shi
- Department of Biochemistry and Molecular Biology (S.X., L.S.), Tianjin Medical University, China.,National Clinical Research Center for Blood Diseases; Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China (H.L., L.S., D.A.)
| | - Yi Zhu
- State Key Laboratory of Experimental Hematology, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education) and Department of Physiology and Pathophysiology, Tianjin Key Laboratory of Metabolic Diseases (C.Z., T.Z., Z.C., M.Y., B.L., H.L., C.W., Y.Z., D.A.), Tianjin Medical University, China
| | - Ding Ai
- State Key Laboratory of Experimental Hematology, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education) and Department of Physiology and Pathophysiology, Tianjin Key Laboratory of Metabolic Diseases (C.Z., T.Z., Z.C., M.Y., B.L., H.L., C.W., Y.Z., D.A.), Tianjin Medical University, China.,National Clinical Research Center for Blood Diseases; Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China (H.L., L.S., D.A.)
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Bi J, Zhang J, Ren Y, Du Z, Zhang Y, Liu C, Wang Y, Zhang L, Shi Z, Wu Z, Lv Y, Wu R. Exercise hormone irisin mitigates endothelial barrier dysfunction and microvascular leakage-related diseases. JCI Insight 2020; 5:e136277. [PMID: 32516137 PMCID: PMC7406290 DOI: 10.1172/jci.insight.136277] [Citation(s) in RCA: 52] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2020] [Accepted: 06/03/2020] [Indexed: 01/10/2023] Open
Abstract
Increased microvascular leakage is a cardinal feature of many critical diseases. Regular exercise is associated with improved endothelial function and reduced risk of cardiovascular disease. Irisin, secreted during exercise, contributes to many health benefits of exercise. However, the effects of irisin on endothelial function and microvascular leakage remain unknown. In this study, we found that irisin remarkably strengthened endothelial junctions and barrier function via binding to integrin αVβ5 receptor in LPS-treated endothelial cells. The beneficial effect of irisin was associated with suppression of the Src-MLCK-β-catenin pathway, activation of the AMPK-Cdc42/Rac1 pathway, and improvement of mitochondrial function. In preclinical models of microvascular leakage, exogenous irisin improved pulmonary function, decreased lung edema and injury, suppressed inflammation, and increased survival. In ARDS patients, serum irisin levels were decreased and inversely correlated with disease severity and mortality. In conclusion, irisin enhances endothelial barrier function and mitigates microvascular leakage-related diseases.
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Affiliation(s)
- Jianbin Bi
- National Local Joint Engineering Research Center for Precision Surgery & Regenerative Medicine, Shaanxi Provincial Center for Regenerative Medicine and Surgical Engineering
- Department of Hepatobiliary Surgery
| | - Jia Zhang
- National Local Joint Engineering Research Center for Precision Surgery & Regenerative Medicine, Shaanxi Provincial Center for Regenerative Medicine and Surgical Engineering
- Department of Hepatobiliary Surgery
| | - Yifan Ren
- National Local Joint Engineering Research Center for Precision Surgery & Regenerative Medicine, Shaanxi Provincial Center for Regenerative Medicine and Surgical Engineering
- Department of Hepatobiliary Surgery
| | - Zhaoqing Du
- National Local Joint Engineering Research Center for Precision Surgery & Regenerative Medicine, Shaanxi Provincial Center for Regenerative Medicine and Surgical Engineering
- Department of Hepatobiliary Surgery
| | | | | | - Yawen Wang
- Biobank
- Department of Laboratory Medicine, and
| | - Lin Zhang
- Department of Laboratory Medicine, and
| | - Zhihong Shi
- Department of Respiratory Medicine, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi Province, China
| | - Zheng Wu
- Department of Hepatobiliary Surgery
| | - Yi Lv
- National Local Joint Engineering Research Center for Precision Surgery & Regenerative Medicine, Shaanxi Provincial Center for Regenerative Medicine and Surgical Engineering
- Department of Hepatobiliary Surgery
| | - Rongqian Wu
- National Local Joint Engineering Research Center for Precision Surgery & Regenerative Medicine, Shaanxi Provincial Center for Regenerative Medicine and Surgical Engineering
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