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1
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El Kamouh MR, Lenck S, Lehericy S, Benveniste H, Thomas JL. Fluid and Waste Clearance in Central Nervous System Health and Diseases. NEURODEGENER DIS 2025:1-22. [PMID: 40334649 DOI: 10.1159/000546018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2024] [Accepted: 04/12/2025] [Indexed: 05/09/2025] Open
Abstract
BACKGROUND In respect to the circulatory system, the central nervous system (CNS) differs from other organs in the body by three main features. First, the CNS is surrounded by a compartment filled with cerebrospinal fluid (CSF). Second, the CNS is devoid of lymphatic vessels, which are found in the dura mater of the meninges. Third, the CNS blood vasculature serves as a scaffold to perivascular spaces allowing CSF to circulate into the CNS parenchyma via the glymphatic system. SUMMARY This review highlights the contribution of the glymphatic system and meningeal lymphatic vasculature to CNS homeostasis and also recapitulates the alterations of glymphatic-meningeal lymphatic systems that have been associated to neurological disorders, especially neurodegenerative diseases. KEY MESSAGE We discuss the controversies and limitations in current research, emphasizing the need for cautious interpretation while highlighting the potential of glymphatic and meningeal lymphatic pathways as therapeutic targets in neurological disorders.
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Affiliation(s)
- Marie-Renee El Kamouh
- Institut du Cerveau-Paris Brain Institute, Hôpital de la Salpêtrière, INSERM, CNRS, Sorbonne Université, Paris, France
| | - Stéphanie Lenck
- Institut du Cerveau-Paris Brain Institute, Hôpital de la Salpêtrière, INSERM, CNRS, Sorbonne Université, Paris, France
- Department of Neuroradiology, AP-HP, Pitié-Salpêtrière Hospital, Paris, France
| | - Stéphane Lehericy
- Institut du Cerveau-Paris Brain Institute, Hôpital de la Salpêtrière, INSERM, CNRS, Sorbonne Université, Paris, France
- Department of Neuroradiology, AP-HP, Pitié-Salpêtrière Hospital, Paris, France
| | - Helene Benveniste
- Department of Anesthesiology, Yale School of Medicine, New Haven, Connecticut, USA
| | - Jean-Léon Thomas
- Institut du Cerveau-Paris Brain Institute, Hôpital de la Salpêtrière, INSERM, CNRS, Sorbonne Université, Paris, France
- Department of Neurology, Yale University School of Medicine, New Haven, Connecticut, USA
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2
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Olaniru OE, Toczyska K, Guccio N, Giera S, Piao X, King AJF, Jones PM, Persaud SJ. Spatiotemporal profiling of adhesion G protein-coupled receptors in developing mouse and human pancreas reveals a role for GPR56 in islet development. Cell Mol Life Sci 2025; 82:129. [PMID: 40137991 PMCID: PMC11947406 DOI: 10.1007/s00018-025-05659-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2024] [Revised: 03/12/2025] [Accepted: 03/14/2025] [Indexed: 03/29/2025]
Abstract
INTRODUCTION G protein-coupled receptors (GPCRs) are cell-surface proteins that are targeted therapeutically for a range of disorders, including diabetes. Adhesion GPCRs (aGPCRs) are the second largest class of the GPCR superfamily and some members of this family have been implicated in appropriate organ development. However, the role of aGPCRs in endocrine pancreas specification is not yet known. METHODS Here, we systematically characterised expression of mRNAs encoding aGPCRs and their ligands in developing mouse and human pancreas using our own and publicly available single-cell RNA sequencing and spatial transcriptomics data, and we conducted qPCR analysis of aGPCR expression in human pancreas at different gestational stages. We then investigated the role of GPR56 (ADGRG1), the most abundant aGPCR in pancreatic endocrine progenitors, in islet development using Gpr56 null mice and their wildtype littermates. RESULTS We demonstrated that aGPCRs are dynamically expressed during mouse and human pancreas development, with specific aGPCR mRNAs expressed in distinct endocrine, endothelial, mesenchymal, acinar, ductal, and immune cell clusters. aGPCR ligand mRNAs were mostly expressed by non-endocrine cells, and the most highly expressed receptor-ligand interacting mRNA pairs were those encoding GPR56 and COL3A1. Deletion of Gpr56 in neonatal mice was associated with an altered α-/β-/δ-cell ratio and reduced β-cell proliferation. CONCLUSION Our data show that aGPCRs are expressed at key stages of human and mouse pancreas endocrine lineage decisions, and analysis of pancreases from Gpr56 knockout mice implicate this aGPCR in the development of a full complement of β-cells.
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Affiliation(s)
- Oladapo E Olaniru
- Department of Diabetes, School of Cardiovascular and Metabolic Medicine & Sciences, King's College London, Guy's Campus, London, SE1 1UL, UK
| | - Klaudia Toczyska
- Department of Diabetes, School of Cardiovascular and Metabolic Medicine & Sciences, King's College London, Guy's Campus, London, SE1 1UL, UK
| | - Nunzio Guccio
- Department of Diabetes, School of Cardiovascular and Metabolic Medicine & Sciences, King's College London, Guy's Campus, London, SE1 1UL, UK
| | - Stefanie Giera
- Department of Medicine, Children's Hospital, Harvard Medical School, Boston, MA, 02115, USA
| | - Xianhua Piao
- Department of Medicine, Children's Hospital, Harvard Medical School, Boston, MA, 02115, USA
- Department of Pediatrics, University of California at San Francisco, San Francisco, CA, USA
| | - Aileen J F King
- Department of Diabetes, School of Cardiovascular and Metabolic Medicine & Sciences, King's College London, Guy's Campus, London, SE1 1UL, UK
| | - Peter M Jones
- Department of Diabetes, School of Cardiovascular and Metabolic Medicine & Sciences, King's College London, Guy's Campus, London, SE1 1UL, UK
| | - Shanta J Persaud
- Department of Diabetes, School of Cardiovascular and Metabolic Medicine & Sciences, King's College London, Guy's Campus, London, SE1 1UL, UK.
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3
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Sebo DJ, Ali I, Fetsko AR, Trimbach AA, Taylor MR. Activation of Wnt/β-catenin in neural progenitor cells regulates blood-brain barrier development and promotes neuroinflammation. Sci Rep 2025; 15:3496. [PMID: 39875426 PMCID: PMC11775206 DOI: 10.1038/s41598-025-85784-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2024] [Accepted: 01/06/2025] [Indexed: 01/30/2025] Open
Abstract
The central nervous system (CNS) requires specialized blood vessels to support neural function within specific microenvironments. During neurovascular development, endothelial Wnt/β-catenin signaling is required for BBB development within the brain parenchyma, whereas fenestrated blood vessels that lack BBB properties do not require Wnt/β-catenin signaling. Here, we used zebrafish to further characterize this phenotypic heterogeneity of the CNS vasculature. Using transgenic reporters of Wnt/β-catenin transcriptional activity, we found an inverse correlation between activated Wnt/β-catenin signaling in endothelial cells (ECs) versus non-ECs within these distinct microenvironments. Our results indicated that the level of Wnt/β-catenin signaling in non-ECs may regulate Wnt/β-catenin activity in adjacent ECs. To further test this concept, we generated a transgenic Tet-On inducible system to drive constitutively active β-catenin expression in neural progenitor cells (NPCs). We found that dose-dependent activation of Wnt/β-catenin in NPCs caused severe deficiency in CNS angiogenesis and BBB development. Additionally, we discovered a significant increase in the proliferation of microglia and infiltration of peripheral neutrophils indicative of a stereotypical neuroinflammatory response. In conclusion, our results demonstrate the importance of proper Wnt/β-catenin signaling within specific CNS microenvironments and highlights the potentially deleterious consequences of aberrant Wnt activation.
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Affiliation(s)
- Dylan J Sebo
- School of Pharmacy, Division of Pharmaceutical Sciences, University of Wisconsin-Madison, Madison, WI, USA
| | - Irshad Ali
- School of Pharmacy, Division of Pharmaceutical Sciences, University of Wisconsin-Madison, Madison, WI, USA
| | - Audrey R Fetsko
- School of Pharmacy, Division of Pharmaceutical Sciences, University of Wisconsin-Madison, Madison, WI, USA
| | - Aubrey A Trimbach
- School of Pharmacy, Division of Pharmaceutical Sciences, University of Wisconsin-Madison, Madison, WI, USA
| | - Michael R Taylor
- School of Pharmacy, Division of Pharmaceutical Sciences, University of Wisconsin-Madison, Madison, WI, USA.
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4
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Lin HH. An Alternative Mode of GPCR Transactivation: Activation of GPCRs by Adhesion GPCRs. Int J Mol Sci 2025; 26:552. [PMID: 39859266 PMCID: PMC11765499 DOI: 10.3390/ijms26020552] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2024] [Revised: 12/31/2024] [Accepted: 01/08/2025] [Indexed: 01/27/2025] Open
Abstract
G protein-coupled receptors (GPCRs), critical for cellular communication and signaling, represent the largest cell surface protein family and play important roles in numerous pathophysiological processes. Consequently, GPCRs have become a primary focus in drug discovery efforts. Beyond their traditional G protein-dependent signaling pathways, GPCRs are also capable of activating alternative signaling mechanisms, including G protein-independent signaling, biased signaling, and signaling crosstalk. A particularly novel signaling mode employed by these receptors is GPCR transactivation, which enables cross-communication between GPCRs and other receptor types. Intriguingly, GPCR transactivation by distinct GPCRs has also been identified. In this review, I provide an overview of the known GPCR transactivation mechanisms and explore recently uncovered GPCR transactivation mediated by adhesion-class GPCRs (aGPCRs). These aGPCR-GPCR transactivation processes regulate unique cell type-specific functions, offering an exciting opportunity to develop therapies that precisely modulate specific GPCR-mediated biological effects.
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Affiliation(s)
- Hsi-Hsien Lin
- Department of Microbiology and Immunology, Graduate School of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan; ; Tel.: +886-03-2118800-3321
- Center for Molecular and Clinical Immunology, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan
- Department of Anatomic Pathology, Chang Gung Memorial Hospital-Linkou, Taoyuan 33305, Taiwan
- Division of Rheumatology, Allergy and Immunology, Chang Gung Memorial Hospital-Keelung, Keelung 20401, Taiwan
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5
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Lin WY, Dong YL, Lin Y, Sunchuri D, Guo ZL. Potential role of G protein‑coupled receptor 124 in cardiovascular and cerebrovascular disease (Review). Exp Ther Med 2025; 29:2. [PMID: 39534284 PMCID: PMC11552082 DOI: 10.3892/etm.2024.12752] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2024] [Accepted: 10/08/2024] [Indexed: 11/16/2024] Open
Abstract
G protein-coupled receptor 124 (GPR124) has a key role in regulating the proliferation and differentiation of endothelial cells, activating inflammatory bodies and promoting angiogenesis and other processes, thus affecting various pathological and physiological processes in the body. GPR124 is vital for promoting the development of the nervous system and maintaining the stability of the blood-brain barrier, and is also associated with cardiovascular and cerebrovascular diseases and cancer. This article will elaborate on the biological information regarding GPR124 published in recent years and its possible related signaling pathways in the field of diseases and provide a reference for further revealing the role of GPR124 in the occurrence and development of diseases.
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Affiliation(s)
- Wan-Yun Lin
- Health Management Center, The First Affiliated Hospital of Hainan Medical University, Haikou, Hainan 570102, P.R. China
- School of Dentistry, Hainan Medical University, Haikou, Hainan 570100, P.R. China
| | - Yu-Lei Dong
- Health Management Center, The First Affiliated Hospital of Hainan Medical University, Haikou, Hainan 570102, P.R. China
- School of Dentistry, Hainan Medical University, Haikou, Hainan 570100, P.R. China
| | - Yang Lin
- School of Dentistry, Hainan Medical University, Haikou, Hainan 570100, P.R. China
| | - Diwas Sunchuri
- School of International Education, Hainan Medical University, Haikou, Hainan 570100, P.R. China
| | - Zhu-Ling Guo
- Health Management Center, The First Affiliated Hospital of Hainan Medical University, Haikou, Hainan 570102, P.R. China
- School of Dentistry, Hainan Medical University, Haikou, Hainan 570100, P.R. China
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6
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Wang P, Luo L, Chen J. Her4.3 + radial glial cells maintain the brain vascular network through activation of Wnt signaling. J Biol Chem 2024; 300:107570. [PMID: 39019216 PMCID: PMC11342778 DOI: 10.1016/j.jbc.2024.107570] [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: 02/20/2024] [Revised: 06/25/2024] [Accepted: 06/29/2024] [Indexed: 07/19/2024] Open
Abstract
During vascular development, radial glial cells (RGCs) regulate vascular patterning in the trunk and contribute to the early differentiation of the blood-brain barrier. Ablation of RGCs results in excessive sprouting vessels or the absence of bilateral vertebral arteries. However, interactions of RGCs with later brain vascular networks after pattern formation remain unknown. Here, we generated a her4.3 transgenic line to label RGCs and applied the metronidazole/nitroreductase system to ablate her4.3+ RGCs. The ablation of her4.3+ RGCs led to the collapse of the cerebral vascular network, disruption of the blood-brain barrier, and downregulation of Wnt signaling. The inhibition of Wnt signaling resulted in the collapse of cerebral vasculature, similar to that caused by her4.3+ RGC ablation. The defects in the maintenance of brain vasculature resulting from the absence of her4.3+ RGCs were partially rescued by the activation of Wnt signaling or overexpression of Wnt7aa or Wnt7bb. Together, our study suggests that her4.3+ RGCs maintain the cerebral vascular network through Wnt signaling.
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Affiliation(s)
- Pengcheng Wang
- Institute of Developmental Biology and Regenerative Medicine, Southwest University, Chongqing, China
| | - Lingfei Luo
- Institute of Developmental Biology and Regenerative Medicine, Southwest University, Chongqing, China; Department of Anaesthesia of Zhongshan Hospital, School of Life Sciences, Fudan University, Shanghai, China
| | - Jingying Chen
- Department of Anaesthesia of Zhongshan Hospital, School of Life Sciences, Fudan University, Shanghai, China.
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7
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Wälchli T, Ghobrial M, Schwab M, Takada S, Zhong H, Suntharalingham S, Vetiska S, Gonzalez DR, Wu R, Rehrauer H, Dinesh A, Yu K, Chen ELY, Bisschop J, Farnhammer F, Mansur A, Kalucka J, Tirosh I, Regli L, Schaller K, Frei K, Ketela T, Bernstein M, Kongkham P, Carmeliet P, Valiante T, Dirks PB, Suva ML, Zadeh G, Tabar V, Schlapbach R, Jackson HW, De Bock K, Fish JE, Monnier PP, Bader GD, Radovanovic I. Single-cell atlas of the human brain vasculature across development, adulthood and disease. Nature 2024; 632:603-613. [PMID: 38987604 PMCID: PMC11324530 DOI: 10.1038/s41586-024-07493-y] [Citation(s) in RCA: 30] [Impact Index Per Article: 30.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2021] [Accepted: 04/30/2024] [Indexed: 07/12/2024]
Abstract
A broad range of brain pathologies critically relies on the vasculature, and cerebrovascular disease is a leading cause of death worldwide. However, the cellular and molecular architecture of the human brain vasculature remains incompletely understood1. Here we performed single-cell RNA sequencing analysis of 606,380 freshly isolated endothelial cells, perivascular cells and other tissue-derived cells from 117 samples, from 68 human fetuses and adult patients to construct a molecular atlas of the developing fetal, adult control and diseased human brain vasculature. We identify extensive molecular heterogeneity of the vasculature of healthy fetal and adult human brains and across five vascular-dependent central nervous system (CNS) pathologies, including brain tumours and brain vascular malformations. We identify alteration of arteriovenous differentiation and reactivated fetal as well as conserved dysregulated genes and pathways in the diseased vasculature. Pathological endothelial cells display a loss of CNS-specific properties and reveal an upregulation of MHC class II molecules, indicating atypical features of CNS endothelial cells. Cell-cell interaction analyses predict substantial endothelial-to-perivascular cell ligand-receptor cross-talk, including immune-related and angiogenic pathways, thereby revealing a central role for the endothelium within brain neurovascular unit signalling networks. Our single-cell brain atlas provides insights into the molecular architecture and heterogeneity of the developing, adult/control and diseased human brain vasculature and serves as a powerful reference for future studies.
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Affiliation(s)
- Thomas Wälchli
- Group Brain Vasculature and Perivascular Niche, Division of Experimental and Translational Neuroscience, Krembil Brain Institute, Krembil Research Institute, Toronto Western Hospital, University Health Network, University of Toronto, Toronto, Ontario, Canada.
- Division of Neurosurgery, Department of Surgery, University of Toronto, Toronto, Ontario, Canada.
- Group of CNS Angiogenesis and Neurovascular Link, Neuroscience Center Zurich, University of Zurich and University Hospital Zurich, Zurich, Switzerland.
- Division of Neurosurgery, University Hospital Zurich, Zurich, Switzerland.
| | - Moheb Ghobrial
- Group Brain Vasculature and Perivascular Niche, Division of Experimental and Translational Neuroscience, Krembil Brain Institute, Krembil Research Institute, Toronto Western Hospital, University Health Network, University of Toronto, Toronto, Ontario, Canada
- Division of Neurosurgery, Department of Surgery, University of Toronto, Toronto, Ontario, Canada
- Group of CNS Angiogenesis and Neurovascular Link, Neuroscience Center Zurich, University of Zurich and University Hospital Zurich, Zurich, Switzerland
- Division of Neurosurgery, University Hospital Zurich, Zurich, Switzerland
- Laboratory of Exercise and Health, Institute of Exercise and Health, Department of Health Sciences and Technology; Swiss Federal Institute of Technology (ETH Zurich), Zurich, Switzerland
| | - Marc Schwab
- Group Brain Vasculature and Perivascular Niche, Division of Experimental and Translational Neuroscience, Krembil Brain Institute, Krembil Research Institute, Toronto Western Hospital, University Health Network, University of Toronto, Toronto, Ontario, Canada
- Division of Neurosurgery, Department of Surgery, University of Toronto, Toronto, Ontario, Canada
- Group of CNS Angiogenesis and Neurovascular Link, Neuroscience Center Zurich, University of Zurich and University Hospital Zurich, Zurich, Switzerland
- Division of Neurosurgery, University Hospital Zurich, Zurich, Switzerland
- Institute for Regenerative Medicine, University of Zurich, Zurich, Switzerland
| | - Shigeki Takada
- Division of Neurosurgery, Department of Surgery, University of Toronto, Toronto, Ontario, Canada
- Department of Neurosurgery, Kyoto University Graduate School of Medicine, Kyoto, Japan
- Division of Experimental and Translational Neuroscience, Krembil Brain Institute, Krembil Research Institute, Toronto Western Hospital, University Health Network, University of Toronto, Toronto, Ontario, Canada
| | - Hang Zhong
- Group Brain Vasculature and Perivascular Niche, Division of Experimental and Translational Neuroscience, Krembil Brain Institute, Krembil Research Institute, Toronto Western Hospital, University Health Network, University of Toronto, Toronto, Ontario, Canada
- Division of Neurosurgery, Department of Surgery, University of Toronto, Toronto, Ontario, Canada
- Group of CNS Angiogenesis and Neurovascular Link, Neuroscience Center Zurich, University of Zurich and University Hospital Zurich, Zurich, Switzerland
- Division of Neurosurgery, University Hospital Zurich, Zurich, Switzerland
- Laboratory of Exercise and Health, Institute of Exercise and Health, Department of Health Sciences and Technology; Swiss Federal Institute of Technology (ETH Zurich), Zurich, Switzerland
| | - Samuel Suntharalingham
- Group Brain Vasculature and Perivascular Niche, Division of Experimental and Translational Neuroscience, Krembil Brain Institute, Krembil Research Institute, Toronto Western Hospital, University Health Network, University of Toronto, Toronto, Ontario, Canada
- Division of Neurosurgery, Department of Surgery, University of Toronto, Toronto, Ontario, Canada
- Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Sandra Vetiska
- Division of Neurosurgery, Department of Surgery, University of Toronto, Toronto, Ontario, Canada
- Division of Experimental and Translational Neuroscience, Krembil Brain Institute, Krembil Research Institute, Toronto Western Hospital, University Health Network, University of Toronto, Toronto, Ontario, Canada
| | | | - Ruilin Wu
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada
- Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada
| | - Hubert Rehrauer
- Functional Genomics Center Zurich, ETH Zurich/University of Zurich, Zurich, Switzerland
| | - Anuroopa Dinesh
- The Lunenfeld-Tanenbaum Research Institute, Mount Sinai Health System, Toronto, Ontario, Canada
| | - Kai Yu
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada
- Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada
| | - Edward L Y Chen
- The Lunenfeld-Tanenbaum Research Institute, Mount Sinai Health System, Toronto, Ontario, Canada
- Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada
| | - Jeroen Bisschop
- Group Brain Vasculature and Perivascular Niche, Division of Experimental and Translational Neuroscience, Krembil Brain Institute, Krembil Research Institute, Toronto Western Hospital, University Health Network, University of Toronto, Toronto, Ontario, Canada
- Division of Neurosurgery, Department of Surgery, University of Toronto, Toronto, Ontario, Canada
- Group of CNS Angiogenesis and Neurovascular Link, Neuroscience Center Zurich, University of Zurich and University Hospital Zurich, Zurich, Switzerland
- Division of Neurosurgery, University Hospital Zurich, Zurich, Switzerland
- Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Fiona Farnhammer
- Group Brain Vasculature and Perivascular Niche, Division of Experimental and Translational Neuroscience, Krembil Brain Institute, Krembil Research Institute, Toronto Western Hospital, University Health Network, University of Toronto, Toronto, Ontario, Canada
- Division of Neurosurgery, Department of Surgery, University of Toronto, Toronto, Ontario, Canada
- Group of CNS Angiogenesis and Neurovascular Link, Neuroscience Center Zurich, University of Zurich and University Hospital Zurich, Zurich, Switzerland
- Division of Neurosurgery, University Hospital Zurich, Zurich, Switzerland
- Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Ann Mansur
- Division of Neurosurgery, Department of Surgery, University of Toronto, Toronto, Ontario, Canada
- Division of Experimental and Translational Neuroscience, Krembil Brain Institute, Krembil Research Institute, Toronto Western Hospital, University Health Network, University of Toronto, Toronto, Ontario, Canada
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada
| | - Joanna Kalucka
- Department of Biomedicine, Aarhus University, Aarhus, Denmark
| | - Itay Tirosh
- Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel
| | - Luca Regli
- Division of Neurosurgery, University Hospital Zurich, Zurich, Switzerland
| | - Karl Schaller
- Department of Neurosurgery, University of Geneva Medical Center & Faculty of Medicine, University of Geneva, Geneva, Switzerland
| | - Karl Frei
- Group of CNS Angiogenesis and Neurovascular Link, Neuroscience Center Zurich, University of Zurich and University Hospital Zurich, Zurich, Switzerland
- Division of Neurosurgery, University Hospital Zurich, Zurich, Switzerland
| | - Troy Ketela
- The Donnelly Centre, University of Toronto, Toronto, Ontario, Canada
| | - Mark Bernstein
- Division of Neurosurgery, Department of Surgery, University of Toronto, Toronto, Ontario, Canada
- Division of Neurosurgery, Sprott Department of Surgery, University of Toronto, Toronto, Ontario, Canada
| | - Paul Kongkham
- Division of Neurosurgery, Department of Surgery, University of Toronto, Toronto, Ontario, Canada
- Division of Neurosurgery, Sprott Department of Surgery, University of Toronto, Toronto, Ontario, Canada
- MacFeeters-Hamilton Centre for Neuro-Oncology Research, University Health Network, Toronto, Ontario, Canada
| | - Peter Carmeliet
- Laboratory of Angiogenesis and Vascular Metabolism, Center for Cancer Biology, VIB & Department of Oncology, KU Leuven, Leuven, Belgium
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, P. R. China
- Laboratory of Angiogenesis and Vascular Heterogeneity, Department of Biomedicine, Aarhus University, Aarhus, Denmark
| | - Taufik Valiante
- Division of Neurosurgery, Department of Surgery, University of Toronto, Toronto, Ontario, Canada
- Division of Neurosurgery, Sprott Department of Surgery, University of Toronto, Toronto, Ontario, Canada
- Krembil Brain Institute, Division of Clinical and Computational Neuroscience, Krembil Research Institute, Toronto Western Hospital, University Health Network, University of Toronto, Toronto, Ontario, Canada
- Institute of Biomaterials and Biomedical Engineering and Electrical and Computer Engineering, University of Toronto, Toronto, Ontario, Canada
- Institute of Medical Science Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Peter B Dirks
- Division of Neurosurgery, Department of Surgery, University of Toronto, Toronto, Ontario, Canada
- Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada
- Division of Neurosurgery, Arthur and Sonia Labatt Brain Tumor Research Center, Departments of Surgery and Molecular Genetics, Hospital for Sick Children, Toronto, Ontario, Canada
| | - Mario L Suva
- Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
- Broad Institute of Harvard and MIT, Cambridge, MA, USA
| | - Gelareh Zadeh
- Division of Neurosurgery, Department of Surgery, University of Toronto, Toronto, Ontario, Canada
- Division of Neurosurgery, Sprott Department of Surgery, University of Toronto, Toronto, Ontario, Canada
- Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
| | - Viviane Tabar
- Department of Neurosurgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Ralph Schlapbach
- Functional Genomics Center Zurich, ETH Zurich/University of Zurich, Zurich, Switzerland
| | - Hartland W Jackson
- The Lunenfeld-Tanenbaum Research Institute, Mount Sinai Health System, Toronto, Ontario, Canada
- Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada
- Ontario Institute of Cancer Research, Toronto, Ontario, Canada
| | - Katrien De Bock
- Laboratory of Exercise and Health, Institute of Exercise and Health, Department of Health Sciences and Technology; Swiss Federal Institute of Technology (ETH Zurich), Zurich, Switzerland
| | - Jason E Fish
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada
- Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada
- Peter Munk Cardiac Centre, University Health Network, Toronto, Ontario, Canada
| | - Philippe P Monnier
- Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
- Krembil Research Institute, Vision Division, Krembil Discovery Tower, Toronto, Ontario, Canada
- Department of Ophthalmology and Vision Sciences, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Gary D Bader
- The Lunenfeld-Tanenbaum Research Institute, Mount Sinai Health System, Toronto, Ontario, Canada
- Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada
- The Donnelly Centre, University of Toronto, Toronto, Ontario, Canada
- Department of Computer Science, University of Toronto, Toronto, Ontario, Canada
| | - Ivan Radovanovic
- Division of Neurosurgery, Department of Surgery, University of Toronto, Toronto, Ontario, Canada
- Division of Experimental and Translational Neuroscience, Krembil Brain Institute, Krembil Research Institute, Toronto Western Hospital, University Health Network, University of Toronto, Toronto, Ontario, Canada
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada
- Division of Neurosurgery, Sprott Department of Surgery, University of Toronto, Toronto, Ontario, Canada
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8
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Fazio A, Neri I, Koufi FD, Marvi MV, Galvani A, Evangelisti C, McCubrey JA, Cocco L, Manzoli L, Ratti S. Signaling Role of Pericytes in Vascular Health and Tissue Homeostasis. Int J Mol Sci 2024; 25:6592. [PMID: 38928298 PMCID: PMC11203602 DOI: 10.3390/ijms25126592] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2024] [Revised: 06/07/2024] [Accepted: 06/10/2024] [Indexed: 06/28/2024] Open
Abstract
Pericytes are multipotent cells embedded within the vascular system, primarily surrounding capillaries and microvessels where they closely interact with endothelial cells. These cells are known for their intriguing properties due to their heterogeneity in tissue distribution, origin, and multifunctional capabilities. Specifically, pericytes are essential in regulating blood flow, promoting angiogenesis, and supporting tissue homeostasis and regeneration. These multifaceted roles draw on pericytes' remarkable ability to respond to biochemical cues, interact with neighboring cells, and adapt to changing environmental conditions. This review aims to summarize existing knowledge on pericytes, emphasizing their versatility and involvement in vascular integrity and tissue health. In particular, a comprehensive view of the major signaling pathways, such as PDGFβ/ PDGFRβ, TGF-β, FOXO and VEGF, along with their downstream targets, which coordinate the behavior of pericytes in preserving vascular integrity and promoting tissue regeneration, will be discussed. In this light, a deeper understanding of the complex signaling networks defining the phenotype of pericytes in healthy tissues is crucial for the development of targeted therapies in vascular and degenerative diseases.
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Affiliation(s)
- Antonietta Fazio
- Department of Biomedical and Neuromotor Sciences, University of Bologna, Via Irnerio 48, 40126 Bologna, Italy; (A.F.); (I.N.); (F.-D.K.); (M.V.M.); (A.G.); (C.E.); (L.C.); (L.M.)
| | - Irene Neri
- Department of Biomedical and Neuromotor Sciences, University of Bologna, Via Irnerio 48, 40126 Bologna, Italy; (A.F.); (I.N.); (F.-D.K.); (M.V.M.); (A.G.); (C.E.); (L.C.); (L.M.)
| | - Foteini-Dionysia Koufi
- Department of Biomedical and Neuromotor Sciences, University of Bologna, Via Irnerio 48, 40126 Bologna, Italy; (A.F.); (I.N.); (F.-D.K.); (M.V.M.); (A.G.); (C.E.); (L.C.); (L.M.)
| | - Maria Vittoria Marvi
- Department of Biomedical and Neuromotor Sciences, University of Bologna, Via Irnerio 48, 40126 Bologna, Italy; (A.F.); (I.N.); (F.-D.K.); (M.V.M.); (A.G.); (C.E.); (L.C.); (L.M.)
| | - Andrea Galvani
- Department of Biomedical and Neuromotor Sciences, University of Bologna, Via Irnerio 48, 40126 Bologna, Italy; (A.F.); (I.N.); (F.-D.K.); (M.V.M.); (A.G.); (C.E.); (L.C.); (L.M.)
- Department of Biomolecular Sciences, University of Urbino “Carlo Bo”, 61029 Urbino, Italy
| | - Camilla Evangelisti
- Department of Biomedical and Neuromotor Sciences, University of Bologna, Via Irnerio 48, 40126 Bologna, Italy; (A.F.); (I.N.); (F.-D.K.); (M.V.M.); (A.G.); (C.E.); (L.C.); (L.M.)
| | - James A. McCubrey
- Department of Microbiology and Immunology, Brody School of Medicine, East Carolina University, Greenville, NC 27834, USA;
| | - Lucio Cocco
- Department of Biomedical and Neuromotor Sciences, University of Bologna, Via Irnerio 48, 40126 Bologna, Italy; (A.F.); (I.N.); (F.-D.K.); (M.V.M.); (A.G.); (C.E.); (L.C.); (L.M.)
| | - Lucia Manzoli
- Department of Biomedical and Neuromotor Sciences, University of Bologna, Via Irnerio 48, 40126 Bologna, Italy; (A.F.); (I.N.); (F.-D.K.); (M.V.M.); (A.G.); (C.E.); (L.C.); (L.M.)
| | - Stefano Ratti
- Department of Biomedical and Neuromotor Sciences, University of Bologna, Via Irnerio 48, 40126 Bologna, Italy; (A.F.); (I.N.); (F.-D.K.); (M.V.M.); (A.G.); (C.E.); (L.C.); (L.M.)
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9
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Yuki K, Vallon M, Ding J, Rada CC, Tang AT, Vilches-Moure JG, McCormick AK, Henao Echeverri MF, Alwahabi S, Braunger BM, Ergün S, Kahn ML, Kuo CJ. GPR124 regulates murine brain embryonic angiogenesis and BBB formation by an intracellular domain-independent mechanism. Development 2024; 151:dev202794. [PMID: 38682276 PMCID: PMC11213517 DOI: 10.1242/dev.202794] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2024] [Accepted: 04/18/2024] [Indexed: 05/01/2024]
Abstract
The GPR124/RECK/WNT7 pathway is an essential regulator of CNS angiogenesis and blood-brain barrier (BBB) function. GPR124, a brain endothelial adhesion seven-pass transmembrane protein, associates with RECK, which binds and stabilizes newly synthesized WNT7 that is transferred to frizzled (FZD) to initiate canonical β-catenin signaling. GPR124 remains enigmatic: although its extracellular domain (ECD) is essential, the poorly conserved intracellular domain (ICD) appears to be variably required in mammals versus zebrafish, potentially via adaptor protein bridging of GPR124 and FZD ICDs. GPR124 ICD deletion impairs zebrafish angiogenesis, but paradoxically retains WNT7 signaling upon mammalian transfection. We thus investigated GPR124 ICD function using the mouse deletion mutant Gpr124ΔC. Despite inefficiently expressed GPR124ΔC protein, Gpr124ΔC/ΔC mice could be born with normal cerebral cortex angiogenesis, in comparison with Gpr124-/- embryonic lethality, forebrain avascularity and hemorrhage. Gpr124ΔC/ΔC vascular phenotypes were restricted to sporadic ganglionic eminence angiogenic defects, attributable to impaired GPR124ΔC protein expression. Furthermore, Gpr124ΔC and the recombinant GPR124 ECD rescued WNT7 signaling in culture upon brain endothelial Gpr124 knockdown. Thus, in mice, GPR124-regulated CNS forebrain angiogenesis and BBB function are exerted by ICD-independent functionality, extending the signaling mechanisms used by adhesion seven-pass transmembrane receptors.
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Affiliation(s)
- Kanako Yuki
- Department of Medicine, Division of Hematology, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Mario Vallon
- Department of Medicine, Division of Hematology, Stanford University School of Medicine, Stanford, CA 94305, USA
- Institute of Anatomy and Cell Biology, Julius-Maximilians-University Wuerzburg, 97070 Wuerzburg, Germany
| | - Jie Ding
- Department of Medicine, Division of Hematology, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Cara C. Rada
- Department of Medicine, Division of Hematology, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Alan T. Tang
- Department of Medicine and Cardiovascular Institute, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - José G. Vilches-Moure
- Department of Comparative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Aaron K. McCormick
- Department of Medicine, Division of Hematology, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Maria F. Henao Echeverri
- Department of Medicine, Division of Hematology, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Samira Alwahabi
- Department of Medicine, Division of Hematology, Stanford University School of Medicine, Stanford, CA 94305, USA
| | - Barbara M. Braunger
- Institute of Anatomy and Cell Biology, Julius-Maximilians-University Wuerzburg, 97070 Wuerzburg, Germany
| | - Süleyman Ergün
- Institute of Anatomy and Cell Biology, Julius-Maximilians-University Wuerzburg, 97070 Wuerzburg, Germany
| | - Mark L. Kahn
- Department of Medicine and Cardiovascular Institute, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Calvin J. Kuo
- Department of Medicine, Division of Hematology, Stanford University School of Medicine, Stanford, CA 94305, USA
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10
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Fetsko AR, Sebo DJ, Budzynski LB, Scharbarth A, Taylor MR. IL-1β disrupts the initiation of blood-brain barrier development by inhibiting endothelial Wnt/β-catenin signaling. iScience 2024; 27:109651. [PMID: 38638574 PMCID: PMC11025013 DOI: 10.1016/j.isci.2024.109651] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2023] [Revised: 02/06/2024] [Accepted: 03/29/2024] [Indexed: 04/20/2024] Open
Abstract
During neuroinflammation, the proinflammatory cytokine interleukin-1β (IL-1β) impacts blood-brain barrier (BBB) function by disrupting brain endothelial tight junctions, promoting vascular permeability, and increasing transmigration of immune cells. Here, we examined the effects of Il-1β on the in vivo initiation of BBB development. We generated doxycycline-inducible transgenic zebrafish to secrete Il-1β in the CNS. To validate the utility of our model, we showed Il-1β dose-dependent mortality, recruitment of neutrophils, and expansion of microglia. Using live imaging, we discovered that Il-1β causes a significant reduction in CNS angiogenesis and barriergenesis. To demonstrate specificity, we rescued the Il-1β induced phenotypes by targeting the zebrafish il1r1 gene using CRISPR-Cas9. Mechanistically, we determined that Il-1β disrupts the initiation of BBB development by decreasing Wnt/β-catenin transcriptional activation in brain endothelial cells. Given that several neurodevelopmental disorders are associated with inflammation, our findings support further investigation into the connections between proinflammatory cytokines, neuroinflammation, and neurovascular development.
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Affiliation(s)
- Audrey R. Fetsko
- School of Pharmacy, Division of Pharmaceutical Sciences, University of Wisconsin-Madison, Madison, WI 53705, USA
| | - Dylan J. Sebo
- School of Pharmacy, Division of Pharmaceutical Sciences, University of Wisconsin-Madison, Madison, WI 53705, USA
| | - Lilyana B. Budzynski
- School of Pharmacy, Pharmacology and Toxicology Program, University of Wisconsin-Madison, Madison, WI 53705, USA
| | - Alli Scharbarth
- School of Pharmacy, Pharmacology and Toxicology Program, University of Wisconsin-Madison, Madison, WI 53705, USA
| | - Michael R. Taylor
- School of Pharmacy, Division of Pharmaceutical Sciences, University of Wisconsin-Madison, Madison, WI 53705, USA
- School of Pharmacy, Pharmacology and Toxicology Program, University of Wisconsin-Madison, Madison, WI 53705, USA
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11
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Xu Y, Fang X, Zhao Z, Wu H, Fan H, Zhang Y, Meng Q, Rong Q, Fukunaga K, Guo Q, Liu Q. GPR124 induces NLRP3 inflammasome-mediated pyroptosis in endothelial cells during ischemic injury. Eur J Pharmacol 2024; 962:176228. [PMID: 38042462 DOI: 10.1016/j.ejphar.2023.176228] [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: 06/17/2023] [Revised: 11/25/2023] [Accepted: 11/27/2023] [Indexed: 12/04/2023]
Abstract
OBJECTIVE G protein-coupled receptor 124 (GPR124) regulates central nervous system angiogenesis and blood-brain barrier (BBB) integrity, and its deficiency aggravates BBB breakdown and hemorrhagic transformation in ischemic mice. However, excessive GPR124 expression promotes inflammation in atherosclerotic mice. In this study, we aimed to elucidate the role of GPR124 in hypoxia/ischemia-induced cerebrovascular endothelial cell injury. METHODS bEnd.3 cells were exposed to oxygen-glucose deprivation (OGD), and time-dependent changes in GPR124 mRNA and protein expression were evaluated using reverse transcription-polymerase chain reaction (RT-PCR) and Western blotting. The effects of GPR124 overexpression or knockdown on the expression of pyroptosis-related genes were assessed at the mRNA and protein levels. Tadehaginoside (TA) was screened as a potential small molecule targeting GPR124, and its effects on pyroptosis-related signaling pathways were investigated. Finally, the therapeutic efficacy of TA was evaluated using a rat model of transient middle cerebral artery occlusion/reperfusion (tMCAO/R). RESULTS During OGD, the expression of GPR124 initially increased and then decreased over time, with the highest levels observed 1 h after OGD. The overexpression of GPR124 enhanced the OGD-induced expression of NLRP3, Caspase-1, and Gasdermin D (GSDMD) in bEnd.3 cells, whereas GPR124 knockdown reduced pyroptosis. Additionally, TA exhibited a high targeting ability to GPR124, significantly inhibiting its function and expression and suppressing the expression of pyroptosis-related proteins during OGD. Furthermore, TA treatment significantly reduced the cerebral infarct volume and pyroptotic signaling in tMCAO/R rats. CONCLUSIONS Our findings suggest that GPR124 mediates pyroptotic signaling in endothelial cells during the early stages of hypoxia/ischemia, thereby exacerbating ischemic injury.
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Affiliation(s)
- Yiqian Xu
- Department of Pharmacy & Engineering Research Center of Tropical Medicine Innovation and Transformation, Ministry of Education, The First Affiliated Hospital of Hainan Medical University, Haikou 570102, China
| | - Xingyue Fang
- Department of Pharmacy & Engineering Research Center of Tropical Medicine Innovation and Transformation, Ministry of Education, The First Affiliated Hospital of Hainan Medical University, Haikou 570102, China
| | - Zhenqiang Zhao
- Key Laboratory of Brain Science Research & Transformation in Tropical Environment of Hainan Province, Hainan Medical University, Haikou 571199, China
| | - Haolin Wu
- Department of Pharmacy & Engineering Research Center of Tropical Medicine Innovation and Transformation, Ministry of Education, The First Affiliated Hospital of Hainan Medical University, Haikou 570102, China
| | - Haofei Fan
- Key Laboratory of Brain Science Research & Transformation in Tropical Environment of Hainan Province, Hainan Medical University, Haikou 571199, China
| | - Ya Zhang
- Key Laboratory of Tropical Translational Medicine of Ministry of Education, College of Biomedical Information and Engineering, Hainan Women and Children's Medical Center, Hainan Medical University, Haikou 571199, China
| | - Qingwen Meng
- Department of Pharmacology, School of Basic and Life Science, Hainan Medical University, Haikou 571199, China
| | - Qiongwen Rong
- Key Laboratory of Brain Science Research & Transformation in Tropical Environment of Hainan Province, Hainan Medical University, Haikou 571199, China
| | - Kohji Fukunaga
- Department of CNS Drug Innovation, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, 980-8578, Japan
| | - Qingyun Guo
- Department of Pharmacology, School of Basic and Life Science, Hainan Medical University, Haikou 571199, China; Key Laboratory of Brain Science Research & Transformation in Tropical Environment of Hainan Province, Hainan Medical University, Haikou 571199, China.
| | - Qibing Liu
- Department of Pharmacy & Engineering Research Center of Tropical Medicine Innovation and Transformation, Ministry of Education, The First Affiliated Hospital of Hainan Medical University, Haikou 570102, China; Department of Pharmacology, School of Basic and Life Science, Hainan Medical University, Haikou 571199, China.
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12
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Su C, Miao J, Guo J. The relationship between TGF-β1 and cognitive function in the brain. Brain Res Bull 2023; 205:110820. [PMID: 37979810 DOI: 10.1016/j.brainresbull.2023.110820] [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: 09/13/2023] [Revised: 11/05/2023] [Accepted: 11/15/2023] [Indexed: 11/20/2023]
Abstract
Transforming growth factor-β1 (TGF-β1), a multifunctional cytokine, plays a pivotal role in synaptic formation, plasticity, and neurovascular unit regulation. This review highlights TGF-β1's potential impact on cognitive function, particularly in the context of neurodegenerative disorders. However, despite the growing body of evidence, a comprehensive understanding of TGF-β1's precise role remains elusive. Further research is essential to unravel the complex mechanisms through which TGF-β1 influences cognitive function and to explore therapeutic avenues for targeting TGF-β1 in neurodegenerative conditions. This investigation sheds light on TGF-β1's contribution to cognitive function and offers prospects for innovative treatments and interventions. This review delves into the intricate relationship between TGF-β1 and cognitive function.
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Affiliation(s)
- Chen Su
- Department of Neurology, First Hospital of Shanxi Medical University, Taiyuan, Shanxi Province 030000, China
| | - Jie Miao
- Department of Neurology, First Hospital of Shanxi Medical University, Taiyuan, Shanxi Province 030000, China
| | - Junhong Guo
- Department of Neurology, First Hospital of Shanxi Medical University, Taiyuan, Shanxi Province 030000, China.
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13
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Lin HH. Functional partnerships between GPI-anchored proteins and adhesion GPCRs. Bioessays 2023; 45:e2300115. [PMID: 37526334 DOI: 10.1002/bies.202300115] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2023] [Revised: 07/19/2023] [Accepted: 07/25/2023] [Indexed: 08/02/2023]
Abstract
Specific extracellular interaction between glycophosphatidylinositol (GPI)-anchored proteins and adhesion G protein-coupled receptors (aGPCRs) plays an important role in unique biological functions. GPI-anchored proteins are derived from a novel post-translational modification of single-span membrane molecules, while aGPCRs are bona fide seven-span transmembrane proteins with a long extracellular domain. Although various members of the two structurally-distinct protein families are known to be involved in a wide range of biological processes, many remain as orphans. Interestingly, accumulating evidence has pointed to a complex interaction and functional synergy between these two protein families. I discuss herein current understanding of specific functional partnerships between GPI-anchored proteins and aGPCRs.
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Affiliation(s)
- Hsi-Hsien Lin
- Department of Microbiology and Immunology, College of Medicine, Chang Gung University, Taoyuan, Taiwan
- Graduate School of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan
- Department of Anatomic Pathology, Chang Gung Memorial Hospital-Linkou, Taoyuan, Taiwan
- Division of Rheumatology, Allergy, and Immunology, Chang Gung Memorial Hospital-Keelung, Keelung, Taiwan
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14
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Shu J, Wang C, Tao Y, Wang S, Cheng F, Zhang Y, Shi K, Xia K, Wang R, Wang J, Yu C, Chen J, Huang X, Xu H, Zhou X, Wu H, Liang C, Chen Q, Yan S, Li F. Thermosensitive hydrogel-based GPR124 delivery strategy for rebuilding blood-spinal cord barrier. Bioeng Transl Med 2023; 8:e10561. [PMID: 37693060 PMCID: PMC10486335 DOI: 10.1002/btm2.10561] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2022] [Revised: 05/20/2023] [Accepted: 05/25/2023] [Indexed: 09/12/2023] Open
Abstract
Spinal cord injury (SCI) causes blood-spinal cord barrier (BSCB) disruption, leading to secondary damage, such as hemorrhagic infiltration, inflammatory response, and neuronal cell death. It is of great significance to rebuild the BSCB at the early stage of SCI to alleviate the secondary injury for better prognosis. Yet, current research involved in the reconstruction of BSCB is insufficient. Accordingly, we provide a thermosensitive hydrogel-based G protein-coupled receptor 124 (GPR124) delivery strategy for rebuilding BSCB. Herein, we firstly found that the expression of GPR124 decreased post-SCI and demonstrated that treatment with recombinant GPR124 could partially alleviate the disruption of BSCB post-SCI by restoring tight junctions (TJs) and promoting migration and tube formation of endothelial cells. Interestingly, GPR124 could also boost the energy metabolism of endothelial cells. However, the absence of physicochemical stability restricted the wide usage of GPR124. Hence, we fabricated a thermosensitive heparin-poloxamer (HP) hydrogel that demonstrated sustained GPR124 production and maintained the bioactivity of GPR124 (HP@124) for rebuilding the BSCB and eventually enhancing functional motor recovery post-SCI. HP@124 hydrogel can encapsulate GPR124 at the lesion site by injection, providing prolonged release, preserving wounded tissues, and filling injured tissue cavities. Consequently, it induces synergistically efficient integrated regulation by blocking BSCB rupture, decreasing fibrotic scar formation, minimizing inflammatory response, boosting remyelination, and regenerating axons. Mechanistically, giving GPR124 activates energy metabolism via elevating the expression of phosphoenolpyruvate carboxykinase 2 (PCK2), and eventually restores the poor state of endothelial cells. This research demonstrated that early intervention by combining GPR124 with bioactive multifunctional hydrogel may have tremendous promise for restoring locomotor recovery in patients with central nervous system disorders, in addition to a translational approach for the medical therapy of SCI.
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Affiliation(s)
- Jiawei Shu
- International Institutes of MedicineThe Fourth Affiliated Hospital, Zhejiang University School of MedicineYiwuZhejiangPeople's Republic of China
- Department of Orthopedics SurgeryThe Second Affiliated Hospital, School of Medicine, Zhejiang UniversityHangzhouZhejiangPeople's Republic of China
- Orthopedics Research Institute of Zhejiang University, Zhejiang UniversityHangzhouZhejiangPeople's Republic of China
- Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang ProvinceHangzhouZhejiangPeople's Republic of China
| | - Chenggui Wang
- The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical UniversityWenzhouZhejiangPeople's Republic of China
| | - Yiqing Tao
- Department of Orthopedics SurgeryThe Second Affiliated Hospital, School of Medicine, Zhejiang UniversityHangzhouZhejiangPeople's Republic of China
- Orthopedics Research Institute of Zhejiang University, Zhejiang UniversityHangzhouZhejiangPeople's Republic of China
- Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang ProvinceHangzhouZhejiangPeople's Republic of China
| | - Shaoke Wang
- Department of Orthopedics SurgeryThe Second Affiliated Hospital, School of Medicine, Zhejiang UniversityHangzhouZhejiangPeople's Republic of China
- Orthopedics Research Institute of Zhejiang University, Zhejiang UniversityHangzhouZhejiangPeople's Republic of China
- Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang ProvinceHangzhouZhejiangPeople's Republic of China
| | - Feng Cheng
- Department of Orthopedics SurgeryThe Second Affiliated Hospital, School of Medicine, Zhejiang UniversityHangzhouZhejiangPeople's Republic of China
- Orthopedics Research Institute of Zhejiang University, Zhejiang UniversityHangzhouZhejiangPeople's Republic of China
- Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang ProvinceHangzhouZhejiangPeople's Republic of China
| | - Yuang Zhang
- Department of Orthopedics SurgeryThe Second Affiliated Hospital, School of Medicine, Zhejiang UniversityHangzhouZhejiangPeople's Republic of China
- Orthopedics Research Institute of Zhejiang University, Zhejiang UniversityHangzhouZhejiangPeople's Republic of China
- Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang ProvinceHangzhouZhejiangPeople's Republic of China
| | - Kesi Shi
- Department of Orthopedics SurgeryThe Second Affiliated Hospital, School of Medicine, Zhejiang UniversityHangzhouZhejiangPeople's Republic of China
- Orthopedics Research Institute of Zhejiang University, Zhejiang UniversityHangzhouZhejiangPeople's Republic of China
- Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang ProvinceHangzhouZhejiangPeople's Republic of China
| | - Kaishun Xia
- Department of Orthopedics SurgeryThe Second Affiliated Hospital, School of Medicine, Zhejiang UniversityHangzhouZhejiangPeople's Republic of China
- Orthopedics Research Institute of Zhejiang University, Zhejiang UniversityHangzhouZhejiangPeople's Republic of China
- Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang ProvinceHangzhouZhejiangPeople's Republic of China
| | - Ronghao Wang
- Department of Orthopedics SurgeryThe Second Affiliated Hospital, School of Medicine, Zhejiang UniversityHangzhouZhejiangPeople's Republic of China
- Orthopedics Research Institute of Zhejiang University, Zhejiang UniversityHangzhouZhejiangPeople's Republic of China
- Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang ProvinceHangzhouZhejiangPeople's Republic of China
| | - Jingkai Wang
- Department of Orthopedics SurgeryThe Second Affiliated Hospital, School of Medicine, Zhejiang UniversityHangzhouZhejiangPeople's Republic of China
- Orthopedics Research Institute of Zhejiang University, Zhejiang UniversityHangzhouZhejiangPeople's Republic of China
- Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang ProvinceHangzhouZhejiangPeople's Republic of China
| | - Chao Yu
- Department of Orthopedics SurgeryThe Second Affiliated Hospital, School of Medicine, Zhejiang UniversityHangzhouZhejiangPeople's Republic of China
- Orthopedics Research Institute of Zhejiang University, Zhejiang UniversityHangzhouZhejiangPeople's Republic of China
- Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang ProvinceHangzhouZhejiangPeople's Republic of China
| | - Jiangjie Chen
- Department of Orthopedics SurgeryThe Second Affiliated Hospital, School of Medicine, Zhejiang UniversityHangzhouZhejiangPeople's Republic of China
- Orthopedics Research Institute of Zhejiang University, Zhejiang UniversityHangzhouZhejiangPeople's Republic of China
- Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang ProvinceHangzhouZhejiangPeople's Republic of China
| | - Xianpeng Huang
- Department of Orthopedics SurgeryThe Second Affiliated Hospital, School of Medicine, Zhejiang UniversityHangzhouZhejiangPeople's Republic of China
- Orthopedics Research Institute of Zhejiang University, Zhejiang UniversityHangzhouZhejiangPeople's Republic of China
- Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang ProvinceHangzhouZhejiangPeople's Republic of China
| | - Haibin Xu
- Department of Orthopedics SurgeryThe Second Affiliated Hospital, School of Medicine, Zhejiang UniversityHangzhouZhejiangPeople's Republic of China
- Orthopedics Research Institute of Zhejiang University, Zhejiang UniversityHangzhouZhejiangPeople's Republic of China
- Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang ProvinceHangzhouZhejiangPeople's Republic of China
| | - Xiaopeng Zhou
- Department of Orthopedics SurgeryThe Second Affiliated Hospital, School of Medicine, Zhejiang UniversityHangzhouZhejiangPeople's Republic of China
- Orthopedics Research Institute of Zhejiang University, Zhejiang UniversityHangzhouZhejiangPeople's Republic of China
- Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang ProvinceHangzhouZhejiangPeople's Republic of China
| | - Haobo Wu
- Department of Orthopedics SurgeryThe Second Affiliated Hospital, School of Medicine, Zhejiang UniversityHangzhouZhejiangPeople's Republic of China
- Orthopedics Research Institute of Zhejiang University, Zhejiang UniversityHangzhouZhejiangPeople's Republic of China
- Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang ProvinceHangzhouZhejiangPeople's Republic of China
| | - Chengzhen Liang
- Department of Orthopedics SurgeryThe Second Affiliated Hospital, School of Medicine, Zhejiang UniversityHangzhouZhejiangPeople's Republic of China
- Orthopedics Research Institute of Zhejiang University, Zhejiang UniversityHangzhouZhejiangPeople's Republic of China
- Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang ProvinceHangzhouZhejiangPeople's Republic of China
| | - Qixin Chen
- Department of Orthopedics SurgeryThe Second Affiliated Hospital, School of Medicine, Zhejiang UniversityHangzhouZhejiangPeople's Republic of China
- Orthopedics Research Institute of Zhejiang University, Zhejiang UniversityHangzhouZhejiangPeople's Republic of China
- Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang ProvinceHangzhouZhejiangPeople's Republic of China
| | - Shigui Yan
- International Institutes of MedicineThe Fourth Affiliated Hospital, Zhejiang University School of MedicineYiwuZhejiangPeople's Republic of China
- Department of Orthopedics SurgeryThe Second Affiliated Hospital, School of Medicine, Zhejiang UniversityHangzhouZhejiangPeople's Republic of China
- Orthopedics Research Institute of Zhejiang University, Zhejiang UniversityHangzhouZhejiangPeople's Republic of China
- Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang ProvinceHangzhouZhejiangPeople's Republic of China
| | - Fangcai Li
- Department of Orthopedics SurgeryThe Second Affiliated Hospital, School of Medicine, Zhejiang UniversityHangzhouZhejiangPeople's Republic of China
- Orthopedics Research Institute of Zhejiang University, Zhejiang UniversityHangzhouZhejiangPeople's Republic of China
- Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang ProvinceHangzhouZhejiangPeople's Republic of China
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15
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Parab S, Setten E, Astanina E, Bussolino F, Doronzo G. The tissue-specific transcriptional landscape underlines the involvement of endothelial cells in health and disease. Pharmacol Ther 2023; 246:108418. [PMID: 37088448 DOI: 10.1016/j.pharmthera.2023.108418] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2022] [Revised: 03/23/2023] [Accepted: 04/17/2023] [Indexed: 04/25/2023]
Abstract
Endothelial cells (ECs) that line vascular and lymphatic vessels are being increasingly recognized as important to organ function in health and disease. ECs participate not only in the trafficking of gases, metabolites, and cells between the bloodstream and tissues but also in the angiocrine-based induction of heterogeneous parenchymal cells, which are unique to their specific tissue functions. The molecular mechanisms regulating EC heterogeneity between and within different tissues are modeled during embryogenesis and become fully established in adults. Any changes in adult tissue homeostasis induced by aging, stress conditions, and various noxae may reshape EC heterogeneity and induce specific transcriptional features that condition a functional phenotype. Heterogeneity is sustained via specific genetic programs organized through the combinatory effects of a discrete number of transcription factors (TFs) that, at the single tissue-level, constitute dynamic networks that are post-transcriptionally and epigenetically regulated. This review is focused on outlining the TF-based networks involved in EC specialization and physiological and pathological stressors thought to modify their architecture.
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Affiliation(s)
- Sushant Parab
- Department of Oncology, University of Torino, IT, Italy; Candiolo Cancer Institute-IRCCS-FPO, Candiolo, Torino, IT, Italy
| | - Elisa Setten
- Department of Oncology, University of Torino, IT, Italy; Candiolo Cancer Institute-IRCCS-FPO, Candiolo, Torino, IT, Italy
| | - Elena Astanina
- Candiolo Cancer Institute-IRCCS-FPO, Candiolo, Torino, IT, Italy
| | - Federico Bussolino
- Department of Oncology, University of Torino, IT, Italy; Candiolo Cancer Institute-IRCCS-FPO, Candiolo, Torino, IT, Italy.
| | - Gabriella Doronzo
- Department of Oncology, University of Torino, IT, Italy; Candiolo Cancer Institute-IRCCS-FPO, Candiolo, Torino, IT, Italy
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16
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Rada CC, Yuki K, Ding J, Kuo CJ. Regulation of the Blood-Brain Barrier in Health and Disease. Cold Spring Harb Perspect Med 2023; 13:a041191. [PMID: 36987582 PMCID: PMC10691497 DOI: 10.1101/cshperspect.a041191] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/29/2023]
Abstract
The neurovascular unit is a dynamic microenvironment with tightly controlled signaling and transport coordinated by the blood-brain barrier (BBB). A properly functioning BBB allows sufficient movement of ions and macromolecules to meet the high metabolic demand of the central nervous system (CNS), while protecting the brain from pathogenic and noxious insults. This review describes the main cell types comprising the BBB and unique molecular signatures of these cells. Additionally, major signaling pathways for BBB development and maintenance are highlighted. Finally, we describe the pathophysiology of BBB diseases, their relationship to barrier dysfunction, and identify avenues for therapeutic intervention.
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Affiliation(s)
- Cara C Rada
- Department of Medicine, Division of Hematology, Stanford University School of Medicine, Stanford, California 94305, USA
| | - Kanako Yuki
- Department of Medicine, Division of Hematology, Stanford University School of Medicine, Stanford, California 94305, USA
| | - Jie Ding
- Department of Medicine, Division of Hematology, Stanford University School of Medicine, Stanford, California 94305, USA
| | - Calvin J Kuo
- Department of Medicine, Division of Hematology, Stanford University School of Medicine, Stanford, California 94305, USA
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17
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Wälchli T, Bisschop J, Carmeliet P, Zadeh G, Monnier PP, De Bock K, Radovanovic I. Shaping the brain vasculature in development and disease in the single-cell era. Nat Rev Neurosci 2023; 24:271-298. [PMID: 36941369 PMCID: PMC10026800 DOI: 10.1038/s41583-023-00684-y] [Citation(s) in RCA: 67] [Impact Index Per Article: 33.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/06/2023] [Indexed: 03/23/2023]
Abstract
The CNS critically relies on the formation and proper function of its vasculature during development, adult homeostasis and disease. Angiogenesis - the formation of new blood vessels - is highly active during brain development, enters almost complete quiescence in the healthy adult brain and is reactivated in vascular-dependent brain pathologies such as brain vascular malformations and brain tumours. Despite major advances in the understanding of the cellular and molecular mechanisms driving angiogenesis in peripheral tissues, developmental signalling pathways orchestrating angiogenic processes in the healthy and the diseased CNS remain incompletely understood. Molecular signalling pathways of the 'neurovascular link' defining common mechanisms of nerve and vessel wiring have emerged as crucial regulators of peripheral vascular growth, but their relevance for angiogenesis in brain development and disease remains largely unexplored. Here we review the current knowledge of general and CNS-specific mechanisms of angiogenesis during brain development and in brain vascular malformations and brain tumours, including how key molecular signalling pathways are reactivated in vascular-dependent diseases. We also discuss how these topics can be studied in the single-cell multi-omics era.
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Affiliation(s)
- Thomas Wälchli
- Group of CNS Angiogenesis and Neurovascular Link, Neuroscience Center Zurich, and Division of Neurosurgery, University and University Hospital Zurich, Swiss Federal Institute of Technology (ETH) Zurich, Zurich, Switzerland.
- Division of Neurosurgery, University Hospital Zurich, Zurich, Switzerland.
- Group of Brain Vasculature and Perivascular Niche, Division of Experimental and Translational Neuroscience, Krembil Brain Institute, Krembil Research Institute, Toronto Western Hospital, University Health Network, University of Toronto, Toronto, ON, Canada.
- Division of Neurosurgery, Department of Surgery, Toronto Western Hospital, Toronto, ON, Canada.
| | - Jeroen Bisschop
- Group of CNS Angiogenesis and Neurovascular Link, Neuroscience Center Zurich, and Division of Neurosurgery, University and University Hospital Zurich, Swiss Federal Institute of Technology (ETH) Zurich, Zurich, Switzerland
- Division of Neurosurgery, University Hospital Zurich, Zurich, Switzerland
- Group of Brain Vasculature and Perivascular Niche, Division of Experimental and Translational Neuroscience, Krembil Brain Institute, Krembil Research Institute, Toronto Western Hospital, University Health Network, University of Toronto, Toronto, ON, Canada
- Division of Neurosurgery, Department of Surgery, Toronto Western Hospital, Toronto, ON, Canada
- Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, ON, Canada
| | - Peter Carmeliet
- Laboratory of Angiogenesis and Vascular Metabolism, Center for Cancer Biology, VIB & Department of Oncology, KU Leuven, Leuven, Belgium
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, People's Republic of China
- Laboratory of Angiogenesis and Vascular Heterogeneity, Department of Biomedicine, Aarhus University, Aarhus, Denmark
| | - Gelareh Zadeh
- Division of Neurosurgery, Department of Surgery, Toronto Western Hospital, Toronto, ON, Canada
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
| | - Philippe P Monnier
- Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, ON, Canada
- Donald K. Johnson Research Institute, Krembil Research Institute, Krembil Discovery Tower, Toronto, ON, Canada
- Department of Ophthalmology and Vision Sciences, Faculty of Medicine, University of Toronto, Toronto, ON, Canada
| | - Katrien De Bock
- Laboratory of Exercise and Health, Department of Health Science and Technology, Swiss Federal Institute of Technology (ETH) Zurich, Zurich, Switzerland
| | - Ivan Radovanovic
- Group of Brain Vasculature and Perivascular Niche, Division of Experimental and Translational Neuroscience, Krembil Brain Institute, Krembil Research Institute, Toronto Western Hospital, University Health Network, University of Toronto, Toronto, ON, Canada
- Division of Neurosurgery, Department of Surgery, Toronto Western Hospital, Toronto, ON, Canada
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18
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Fetsko AR, Sebo DJ, Taylor MR. Brain endothelial cells acquire blood-brain barrier properties in the absence of Vegf-dependent CNS angiogenesis. Dev Biol 2023; 494:46-59. [PMID: 36502932 PMCID: PMC9870987 DOI: 10.1016/j.ydbio.2022.11.007] [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: 09/08/2022] [Revised: 11/08/2022] [Accepted: 11/22/2022] [Indexed: 12/13/2022]
Abstract
During neurovascular development, brain endothelial cells (BECs) respond to secreted signals from the neuroectoderm that regulate CNS angiogenesis, the formation of new blood vessels in the brain, and barriergenesis, the acquisition of blood-brain barrier (BBB) properties. Wnt/β-catenin signaling and Vegf signaling are both required for CNS angiogenesis; however, the relationship between these pathways is not understood. Furthermore, while Wnt/β-catenin signaling is essential for barriergenesis, the role of Vegf signaling in this vital process remains unknown. Here, we provide the first direct evidence, to our knowledge, that Vegf signaling is not required for barriergenesis and that activation of Wnt/β-catenin in BECs is independent of Vegf signaling during neurovascular development. Using double transgenic glut1b:mCherry and plvap:EGFP zebrafish (Danio rerio) to visualize the developing brain vasculature, we performed a forward genetic screen and identified a new mutant allele of kdrl, an ortholog of mammalian Vegfr2. The kdrl mutant lacks CNS angiogenesis but, unlike the Wnt/β-catenin pathway mutant gpr124, acquires BBB properties in BECs. To examine Wnt/β-catenin pathway activation in BECs, we chemically inhibited Vegf signaling and found robust expression of the Wnt/β-catenin transcriptional reporter line 7xtcf-Xla.Siam:EGFP. Taken together, our results establish that Vegf signaling is essential for CNS angiogenesis but is not required for Wnt/β-catenin-dependent barriergenesis. Given the clinical significance of either inhibiting pathological angiogenesis or stimulating neovascularization, our study provides valuable new insights that are critical for the development of effective therapies that target the vasculature in neurological disorders.
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Affiliation(s)
- Audrey R Fetsko
- School of Pharmacy, Division of Pharmaceutical Sciences, University of Wisconsin-Madison, Madison, WI, USA
| | - Dylan J Sebo
- School of Pharmacy, Division of Pharmaceutical Sciences, University of Wisconsin-Madison, Madison, WI, USA
| | - Michael R Taylor
- School of Pharmacy, Division of Pharmaceutical Sciences, University of Wisconsin-Madison, Madison, WI, USA.
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19
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Goncalves A, Antonetti DA. Transgenic animal models to explore and modulate the blood brain and blood retinal barriers of the CNS. Fluids Barriers CNS 2022; 19:86. [PMID: 36320068 PMCID: PMC9628113 DOI: 10.1186/s12987-022-00386-0] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Accepted: 10/03/2022] [Indexed: 11/18/2022] Open
Abstract
The unique environment of the brain and retina is tightly regulated by blood-brain barrier and the blood-retinal barrier, respectively, to ensure proper neuronal function. Endothelial cells within these tissues possess distinct properties that allow for controlled passage of solutes and fluids. Pericytes, glia cells and neurons signal to endothelial cells (ECs) to form and maintain the barriers and control blood flow, helping to create the neurovascular unit. This barrier is lost in a wide range of diseases affecting the central nervous system (CNS) and retina such as brain tumors, stroke, dementia, and in the eye, diabetic retinopathy, retinal vein occlusions and age-related macular degeneration to name prominent examples. Recent studies directly link barrier changes to promotion of disease pathology and degradation of neuronal function. Understanding how these barriers form and how to restore these barriers in disease provides an important point for therapeutic intervention. This review aims to describe the fundamentals of the blood-tissue barriers of the CNS and how the use of transgenic animal models led to our current understanding of the molecular framework of these barriers. The review also highlights examples of targeting barrier properties to protect neuronal function in disease states.
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Affiliation(s)
- Andreia Goncalves
- Department of Ophthalmology and Visual Sciences, University of Michigan Kellogg Eye Center, 1000 Wall St Rm, Ann Arbor, MI, 7317, USA
| | - David A Antonetti
- Department of Ophthalmology and Visual Sciences, University of Michigan Kellogg Eye Center, 1000 Wall St Rm, Ann Arbor, MI, 7317, USA.
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20
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Lala T, Hall RA. Adhesion G protein-coupled receptors: structure, signaling, physiology, and pathophysiology. Physiol Rev 2022; 102:1587-1624. [PMID: 35468004 PMCID: PMC9255715 DOI: 10.1152/physrev.00027.2021] [Citation(s) in RCA: 41] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2021] [Revised: 03/11/2022] [Accepted: 04/16/2022] [Indexed: 01/17/2023] Open
Abstract
Adhesion G protein-coupled receptors (AGPCRs) are a family of 33 receptors in humans exhibiting a conserved general structure but diverse expression patterns and physiological functions. The large NH2 termini characteristic of AGPCRs confer unique properties to each receptor and possess a variety of distinct domains that can bind to a diverse array of extracellular proteins and components of the extracellular matrix. The traditional view of AGPCRs, as implied by their name, is that their core function is the mediation of adhesion. In recent years, though, many surprising advances have been made regarding AGPCR signaling mechanisms, activation by mechanosensory forces, and stimulation by small-molecule ligands such as steroid hormones and bioactive lipids. Thus, a new view of AGPCRs has begun to emerge in which these receptors are seen as massive signaling platforms that are crucial for the integration of adhesive, mechanosensory, and chemical stimuli. This review article describes the recent advances that have led to this new understanding of AGPCR function and also discusses new insights into the physiological actions of these receptors as well as their roles in human disease.
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Affiliation(s)
- Trisha Lala
- Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, Georgia
| | - Randy A Hall
- Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, Georgia
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21
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Yin A, Guan X, Zhang JV, Niu J. Focusing on the role of secretin/adhesion (Class B) G protein-coupled receptors in placental development and preeclampsia. Front Cell Dev Biol 2022; 10:959239. [PMID: 36187484 PMCID: PMC9515905 DOI: 10.3389/fcell.2022.959239] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2022] [Accepted: 07/25/2022] [Indexed: 11/13/2022] Open
Abstract
Preeclampsia, a clinical syndrome mainly characterized by hypertension and proteinuria, with a worldwide incidence of 3–8% and high maternal mortality, is a risk factor highly associated with maternal and offspring cardiovascular disease. However, the etiology and pathogenesis of preeclampsia are complicated and have not been fully elucidated. Obesity, immunological diseases and endocrine metabolic diseases are high-risk factors for the development of preeclampsia. Effective methods to treat preeclampsia are lacking, and termination of pregnancy remains the only curative treatment for preeclampsia. The pathogenesis of preeclampsia include poor placentation, uteroplacental malperfusion, oxidative stress, endoplasmic reticulum stress, dysregulated immune tolerance, vascular inflammation and endothelial cell dysfunction. The notion that placenta is the core factor in the pathogenesis of preeclampsia is still prevailing. G protein-coupled receptors, the largest family of membrane proteins in eukaryotes and the largest drug target family to date, exhibit diversity in structure and function. Among them, the secretin/adhesion (Class B) G protein-coupled receptors are essential drug targets for human diseases, such as endocrine diseases and cardiometabolic diseases. Given the great value of the secretin/adhesion (Class B) G protein-coupled receptors in the regulation of cardiovascular system function and the drug target exploration, we summarize the role of these receptors in placental development and preeclampsia, and outlined the relevant pathological mechanisms, thereby providing potential drug targets for preeclampsia treatment.
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Affiliation(s)
- Aiqi Yin
- Department of Obstetrics, Shenzhen Maternity and Child Healthcare Hospital, The First School of Clinical Medicine, Southern Medical University, Shenzhen, China
| | - Xiaonian Guan
- Department of Obstetrics, Shenzhen Maternity and Child Healthcare Hospital, The First School of Clinical Medicine, Southern Medical University, Shenzhen, China
| | - Jian V. Zhang
- Center for Energy Metabolism and Reproduction, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
- Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
- Shenzhen Key Laboratory of Metabolic Health, Shenzhen, China
- *Correspondence: Jian V. Zhang, ; Jianmin Niu,
| | - Jianmin Niu
- Department of Obstetrics, Shenzhen Maternity and Child Healthcare Hospital, The First School of Clinical Medicine, Southern Medical University, Shenzhen, China
- *Correspondence: Jian V. Zhang, ; Jianmin Niu,
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22
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Sato Y, Falcone-Juengert J, Tominaga T, Su H, Liu J. Remodeling of the Neurovascular Unit Following Cerebral Ischemia and Hemorrhage. Cells 2022; 11:2823. [PMID: 36139398 PMCID: PMC9496956 DOI: 10.3390/cells11182823] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2022] [Revised: 08/18/2022] [Accepted: 08/30/2022] [Indexed: 11/23/2022] Open
Abstract
Formulated as a group effort of the stroke community, the transforming concept of the neurovascular unit (NVU) depicts the structural and functional relationship between brain cells and the vascular structure. Composed of both neural and vascular elements, the NVU forms the blood-brain barrier that regulates cerebral blood flow to meet the oxygen demand of the brain in normal physiology and maintain brain homeostasis. Conversely, the dysregulation and dysfunction of the NVU is an essential pathological feature that underlies neurological disorders spanning from chronic neurodegeneration to acute cerebrovascular events such as ischemic stroke and cerebral hemorrhage, which were the focus of this review. We also discussed how common vascular risk factors of stroke predispose the NVU to pathological changes. We synthesized existing literature and first provided an overview of the basic structure and function of NVU, followed by knowledge of how these components remodel in response to ischemic stroke and brain hemorrhage. A greater understanding of the NVU dysfunction and remodeling will enable the design of targeted therapies and provide a valuable foundation for relevant research in this area.
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Affiliation(s)
- Yoshimichi Sato
- Department of Neurological Surgery, UCSF, San Francisco, CA 94158, USA
- Department of Neurological Surgery, SFVAMC, San Francisco, CA 94158, USA
- Department of Neurosurgery, Graduate School of Medicine, Tohoku University, 1-1 Seiryo-machi, Aoba-ku, Sendai 980-8574, Japan
| | - Jaime Falcone-Juengert
- Department of Neurological Surgery, UCSF, San Francisco, CA 94158, USA
- Department of Neurological Surgery, SFVAMC, San Francisco, CA 94158, USA
| | - Teiji Tominaga
- Department of Neurosurgery, Graduate School of Medicine, Tohoku University, 1-1 Seiryo-machi, Aoba-ku, Sendai 980-8574, Japan
| | - Hua Su
- Department of Anesthesia, UCSF, San Francisco, CA 94143, USA
- Center for Cerebrovascular Research, UCSF, San Francisco, CA 94143, USA
| | - Jialing Liu
- Department of Neurological Surgery, UCSF, San Francisco, CA 94158, USA
- Department of Neurological Surgery, SFVAMC, San Francisco, CA 94158, USA
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23
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Abstract
During development, the central nervous system (CNS) vasculature grows to precisely meet the metabolic demands of neurons and glia. In addition, the vast majority of the CNS vasculature acquires a unique set of molecular and cellular properties-collectively referred to as the blood-brain barrier-that minimize passive diffusion of molecules between the blood and the CNS parenchyma. Both of these processes are controlled by signals emanating from neurons and glia. In this review, we describe the nature and mechanisms-of-action of these signals, with an emphasis on vascular endothelial growth factor (VEGF) and beta-catenin (canonical Wnt) signaling, the two best-understood systems that regulate CNS vascular development. We highlight foundational discoveries, interactions between different signaling systems, the integration of genetic and cell biological studies, advances that are of clinical relevance, and questions for future research.
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Affiliation(s)
- Amir Rattner
- Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States;
| | - Yanshu Wang
- Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States; .,Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States
| | - Jeremy Nathans
- Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States; .,Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States.,Departments of Neuroscience and Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States
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24
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Bats ML, Peghaire C, Delobel V, Dufourcq P, Couffinhal T, Duplàa C. Wnt/frizzled Signaling in Endothelium: A Major Player in Blood-Retinal- and Blood-Brain-Barrier Integrity. Cold Spring Harb Perspect Med 2022; 12:a041219. [PMID: 35074794 PMCID: PMC9121893 DOI: 10.1101/cshperspect.a041219] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
The Wnt/frizzled signaling pathway is one of the major regulators of endothelial biology, controlling key cellular activities. Many secreted Wnt ligands have been identified and can initiate diverse signaling via binding to a complex set of Frizzled (Fzd) transmembrane receptors and coreceptors. Roughly, Wnt signaling is subdivided into two pathways: the canonical Wnt/β-catenin signaling pathway whose main downstream effector is the transcriptional coactivator β-catenin, and the noncanonical Wnt signaling pathway, which is subdivided into the Wnt/Ca2+ pathway and the planar cell polarity pathway. Here, we will focus on its cross talk with other angiogenic pathways and on its role in blood-retinal- and blood-brain-barrier formation and its maintenance in a differentiated state. We will unravel how retinal vascular pathologies and neurovascular degenerative diseases result from disruption of the Wnt pathway related to vascular instability, and highlight current research into therapeutic options.
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Affiliation(s)
- Marie-Lise Bats
- Univ. Bordeaux, Inserm, UMR1034, Biology of Cardiovascular Diseases, F-33600 Pessac, France
- Department of Biochemistry, Pellegrin Hospital, University Hospital of Bordeaux, 33076 Bordeaux Cedex, France
| | - Claire Peghaire
- Univ. Bordeaux, Inserm, UMR1034, Biology of Cardiovascular Diseases, F-33600 Pessac, France
| | - Valentin Delobel
- Univ. Bordeaux, Inserm, UMR1034, Biology of Cardiovascular Diseases, F-33600 Pessac, France
| | - Pascale Dufourcq
- Univ. Bordeaux, Inserm, UMR1034, Biology of Cardiovascular Diseases, F-33600 Pessac, France
| | - Thierry Couffinhal
- Univ. Bordeaux, Inserm, UMR1034, Biology of Cardiovascular Diseases, F-33600 Pessac, France
- Centre d'exploration, de prévention et de traitement de l'athérosclérose (CEPTA), CHU Bordeaux, 33000 Bordeaux, France
| | - Cécile Duplàa
- Univ. Bordeaux, Inserm, UMR1034, Biology of Cardiovascular Diseases, F-33600 Pessac, France
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25
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Wang Y, Venkatesh A, Xu J, Xu M, Williams J, Smallwood PM, James A, Nathans J. The WNT7A/WNT7B/GPR124/RECK signaling module plays an essential role in mammalian limb development. Development 2022; 149:275368. [PMID: 35552394 PMCID: PMC9148564 DOI: 10.1242/dev.200340] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2021] [Accepted: 04/20/2022] [Indexed: 12/04/2022]
Abstract
In central nervous system vascular endothelial cells, signaling via the partially redundant ligands WNT7A and WNT7B requires two co-activator proteins, GPR124 and RECK. WNT7A and RECK have been shown previously to play a role in limb development, but the mechanism of RECK action in this context is unknown. The roles of WNT7B and GPR124 in limb development have not been investigated. Using combinations of conventional and/or conditional loss-of-function alleles for mouse Wnt7a, Wnt7b, Gpr124 and Reck, including a Reck allele that codes for a protein that is specifically defective in WNT7A/WNT7B signaling, we show that reductions in ligand and/or co-activator function synergize to cause reduced and dysmorphic limb bone growth. Two additional limb phenotypes – loss of distal Lmx1b expression and ectopic growth of nail-like structures – occur with reduced Wnt7a/Wnt7b gene copy number and, respectively, with Reck mutations and with combined Reck and Gpr124 mutations. A third limb phenotype – bleeding into a digit – occurs with the most severe combinations of Wnt7a/Wnt7b, Reck and Gpr124 mutations. These data imply that the WNT7A/WNT7B-FRIZZLED-LRP5/LRP6-GPR124-RECK signaling system functions as an integral unit in limb development. Summary: Genetic analyses in mice show that the WNT7A/WNT7B-FRIZZLED-LRP5/LRP6-GPR124-RECK signaling system, first defined in the context of CNS angiogenesis and barrier development, also functions as an integral unit in limb development.
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Affiliation(s)
- Yanshu Wang
- Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
- Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Arjun Venkatesh
- Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
- Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Jiajia Xu
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Mingxin Xu
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - John Williams
- Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
- Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Philip M. Smallwood
- Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
- Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Aaron James
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Jeremy Nathans
- Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
- Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
- Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
- Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
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26
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Maharati A, Zanguei AS, Khalili-Tanha G, Moghbeli M. MicroRNAs as the critical regulators of tyrosine kinase inhibitors resistance in lung tumor cells. Cell Commun Signal 2022; 20:27. [PMID: 35264191 PMCID: PMC8905758 DOI: 10.1186/s12964-022-00840-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2021] [Accepted: 02/05/2022] [Indexed: 12/12/2022] Open
Abstract
Lung cancer is the second most common and the leading cause of cancer related deaths globally. Tyrosine Kinase Inhibitors (TKIs) are among the common therapeutic strategies in lung cancer patients, however the treatment process fails in a wide range of patients due to TKIs resistance. Given that the use of anti-cancer drugs can always have side effects on normal tissues, predicting the TKI responses can provide an efficient therapeutic strategy. Therefore, it is required to clarify the molecular mechanisms of TKIs resistance in lung cancer patients. MicroRNAs (miRNAs) are involved in regulation of various pathophysiological cellular processes. In the present review, we discussed the miRNAs that have been associated with TKIs responses in lung cancer. MiRNAs mainly exert their role on TKIs response through regulation of Tyrosine Kinase Receptors (TKRs) and down-stream signaling pathways. This review paves the way for introducing a panel of miRNAs for the prediction of TKIs responses in lung cancer patients.
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