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Zambuto SG, Theriault H, Jain I, Crosby CO, Pintescu I, Chiou N, Oyen ML, Zoldan J, Underhill GH, Harley BAC, Clancy KBH. Endometrial decidualization status modulates endometrial microvascular complexity and trophoblast outgrowth in gelatin methacryloyl hydrogels. NPJ WOMEN'S HEALTH 2024; 2:22. [PMID: 39036057 PMCID: PMC11259096 DOI: 10.1038/s44294-024-00020-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/05/2023] [Accepted: 04/20/2024] [Indexed: 07/23/2024]
Abstract
The endometrium undergoes rapid cycles of vascular growth, remodeling, and breakdown during the menstrual cycle and pregnancy. Decidualization is an endometrial differentiation process driven by steroidal sex hormones that is critical for blastocyst-uterine interfacing and blastocyst implantation. Certain pregnancy disorders may be linked to decidualization processes. However, much remains unknown regarding the role of decidualization and reciprocal trophoblast-endometrial interactions on endometrial angiogenesis and trophoblast invasion. Here, we report an engineered endometrial microvascular network embedded in gelatin hydrogels that displays morphological and functional patterns of decidualization. Vessel complexity and biomolecule secretion are sensitive to decidualization and affect trophoblast motility, but that signaling between endometrial and trophoblast cells was not bi-directional. Although endometrial microvascular network decidualization status influences trophoblast cells, trophoblast cells did not induce structural changes in the endometrial microvascular networks. These findings add to a growing literature that the endometrium has biological agency at the uterine-trophoblast interface during implantation. Finally, we form a stratified endometrial tri-culture model, combining engineered microvascular networks with epithelial cells. These endometrial microvascular networks provide a well-characterized platform to investigate dynamic changes in angiogenesis in response to pathological and physiological endometrial states.
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Affiliation(s)
- Samantha G. Zambuto
- Department of Bioengineering, University of Illinois Urbana-Champaign, Urbana, IL 61801, USA
| | - Hannah Theriault
- Department of Bioengineering, University of Illinois Urbana-Champaign, Urbana, IL 61801, USA
| | - Ishita Jain
- Department of Bioengineering, University of Illinois Urbana-Champaign, Urbana, IL 61801, USA
| | - Cody O. Crosby
- Department of Physics, Southwestern University, Georgetown, TX 78626, USA
- Department of Biomedical Engineering, University of Texas at Austin, Austin, TX 78712, USA
| | - Ioana Pintescu
- Department of Molecular and Cellular Biology, University of Illinois Urbana-Champaign, Urbana, IL 61801, USA
| | - Noah Chiou
- Department of Bioengineering, University of Illinois Urbana-Champaign, Urbana, IL 61801, USA
| | - Michelle L. Oyen
- Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO 63130, USA
- Center for Women’s Health Engineering, Washington University in St. Louis, St. Louis, MO 63130, USA
- Department of Obstetrics and Gynecology, Washington University School of Medicine, St. Louis, MO 63130, USA
| | - Janet Zoldan
- Department of Biomedical Engineering, University of Texas at Austin, Austin, TX 78712, USA
| | - Gregory H. Underhill
- Department of Bioengineering, University of Illinois Urbana-Champaign, Urbana, IL 61801, USA
| | - Brendan A. C. Harley
- Carl R. Woese Institute for Genomic Biology, University of Illinois Urbana-Champaign, Urbana, IL 61801, USA
- Department Chemical and Biomolecular Engineering, University of Illinois Urbana-Champaign, Urbana, IL 61801, USA
- Cancer Center at Illinois, University of Illinois Urbana-Champaign, Urbana, IL 61801, USA
| | - Kathryn B. H. Clancy
- Carl R. Woese Institute for Genomic Biology, University of Illinois Urbana-Champaign, Urbana, IL 61801, USA
- Department of Anthropology, University of Illinois Urbana-Champaign, Urbana, IL 61801, USA
- Beckman Institute for Advanced Science & Technology, University of Illinois Urbana-Champaign, Urbana, IL 61801, USA
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Alshannag F, Zaki RMM, Hemida E, ElBakry MMM, Noureldeen AFH. Endostatin and Cystatin C as Potential Biomarkers for Early Prediction of Preeclampsia. ACS OMEGA 2023; 8:42776-42786. [PMID: 38024766 PMCID: PMC10652833 DOI: 10.1021/acsomega.3c05586] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/31/2023] [Revised: 10/18/2023] [Accepted: 10/19/2023] [Indexed: 12/01/2023]
Abstract
Preeclampsia (PE) is characterized by new onset hypertension and proteinuria. Undoubtedly, some individuals do not fit precisely into this description, and it could be challenging to spot newly developed PE in females who already have hypertension or renal illness. Monitoring the disease's progression enables the optimization of delivery time while minimizing premature births. The current study explores the diagnostic benefits of serum endostatin and cystatin C in addition to serum and urinary magnesium (Mg) and fractional excretion magnesium (FEMg) for early prediction of PE. The population sample included 82 pregnant women divided into 3 groups: normal pregnancy group served as a control (n = 26), nonpreeclampsia (NPE, n = 34) group included pregnant women with one or more risk factors but did not progress to PE, and pregnant women who developed preeclampsia (PE, n = 22) group. Blood samples were withdrawn at two sampling times: at 12th to 16th and 24th to 26th weeks of gestation. Compared to normal pregnancy, results (X̅ ± SD) indicated a significant increase in serum endostatin in NPE at the first sample (10.78 ± 3.63 ng/mL) and the second sample (28.03 ± 3.79 ng/mL), while cystatin C was at the first sample (0.68 ± 0.06 mg/dL) and the second sample (0.71 ± 0.07 mg/dL). In the PE group, the serum endostatin was 18.86 ± 4.37 ng/mL at the first sampling time and 53.56 ± 9.76 ng/mL for the second sample. Serum cystatin C was also elevated in PE with X̅ ± SD equivalent to 0.73 ± 0.08 and 0.89 ± 0.08 mg/dL at the first and second samples, respectively. On the other hand, serum and urinary Mg in addition to FEMg levels did not significantly differ across the groups under study. Receiver operating characteristic (ROC) curve analysis proved that both endostatin and cystatin C could be good indicators for PE. The findings imply that measuring endostatin and cystatin C at early pregnancy and before progression to PE may be effective in detecting the likelihood of PE. Endostatin could be more precise and sensitive in assessing the probability of PE than cystatin C; however, coupling of the two parameters may be promising.
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Affiliation(s)
- Fatima Alshannag
- Biochemistry
Department, Faculty of Science, Ain Shams
University, Cairo 11566, Egypt
| | - Radwa M. M. Zaki
- Obstetrics
and Gynecology Department, Faculty of Medicine, Ain Shams University, Cairo 11566, Egypt
| | - Eman Hemida
- Ain
Shams Specialized Hospital, Cairo 11568, Egypt
| | - Mustafa M. M. ElBakry
- Biochemistry
Department, Faculty of Science, Ain Shams
University, Cairo 11566, Egypt
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Kutikhin AG, Shishkova DK, Velikanova EA, Sinitsky MY, Sinitskaya AV, Markova VE. Endothelial Dysfunction in the Context of Blood–Brain Barrier Modeling. J EVOL BIOCHEM PHYS+ 2022; 58:781-806. [PMID: 35789679 PMCID: PMC9243926 DOI: 10.1134/s0022093022030139] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2022] [Revised: 04/04/2022] [Accepted: 04/05/2022] [Indexed: 01/04/2023]
Abstract
Here, we discuss pathophysiological approaches to the defining
of endothelial dysfunction criteria (i.e., endothelial activation,
impaired endothelial mechanotransduction, endothelial-to-mesenchymal
transition, reduced nitric oxide release, compromised endothelial
integrity, and loss of anti-thrombogenic properties) in different
in vitro and in vivo models. The canonical definition of endothelial
dysfunction includes insufficient production of vasodilators, pro-thrombotic
and pro-inflammatory activation of endothelial cells, and pathologically
increased endothelial permeability. Among the clinical consequences
of endothelial dysfunction are arterial hypertension, macro- and
microangiopathy, and microalbuminuria. We propose to extend the definition
of endothelial dysfunction by adding altered endothelial mechanotransduction
and endothelial-to-mesenchymal transition to its criteria. Albeit
interleukin-6, interleukin-8, and MCP-1/CCL2 dictate the pathogenic
paracrine effects of dysfunctional endothelial cells and are therefore
reliable endothelial dysfunction biomarkers in vitro, they are non-specific
for endothelial cells and cannot be used for the diagnostics of
endothelial dysfunction in vivo. Conceptual improvements in the
existing methods to model endothelial dysfunction, specifically,
in relation to the blood–brain barrier, include endothelial cell
culturing under pulsatile flow, collagen IV coating of flow chambers,
and endothelial lysate collection from the blood vessels of laboratory
animals in situ for the subsequent gene and protein expression profiling.
Combined with the simulation of paracrine effects by using conditioned
medium from dysfunctional endothelial cells, these flow-sensitive
models have a high physiological relevance, bringing the experimental
conditions to the physiological scenario.
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Affiliation(s)
- A. G. Kutikhin
- Research Institute for Complex Issues of Cardiovascular Diseases, Kemerovo, Russia
| | - D. K. Shishkova
- Research Institute for Complex Issues of Cardiovascular Diseases, Kemerovo, Russia
| | - E. A. Velikanova
- Research Institute for Complex Issues of Cardiovascular Diseases, Kemerovo, Russia
| | - M. Yu. Sinitsky
- Research Institute for Complex Issues of Cardiovascular Diseases, Kemerovo, Russia
| | - A. V. Sinitskaya
- Research Institute for Complex Issues of Cardiovascular Diseases, Kemerovo, Russia
| | - V. E. Markova
- Research Institute for Complex Issues of Cardiovascular Diseases, Kemerovo, Russia
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Testing Hypoxia in Pig Meniscal Culture: Biological Role of the Vascular-Related Factors in the Differentiation and Viability of Neonatal Meniscus. Int J Mol Sci 2021; 22:ijms222212465. [PMID: 34830345 PMCID: PMC8617958 DOI: 10.3390/ijms222212465] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2021] [Revised: 11/13/2021] [Accepted: 11/15/2021] [Indexed: 12/13/2022] Open
Abstract
Menisci play an essential role in shock absorption, joint stability, load resistance and its transmission thanks to their conformation. Adult menisci can be divided in three zones based on the vascularization: an avascular inner zone with no blood supply, a fully vascularized outer zone, and an intermediate zone. This organization, in addition to the incomplete knowledge about meniscal biology, composition, and gene expression, makes meniscal regeneration still one of the major challenges both in orthopedics and in tissue engineering. To overcome this issue, we aimed to investigate the role of hypoxia in the differentiation of the three anatomical areas of newborn piglet menisci (anterior horn (A), central body (C), and posterior horn (P)) and its effects on vascular factors. After sample collection, menisci were divided in A, C, P, and they were cultured in vitro under hypoxic (1% O2) and normoxic (21% O2) conditions at four different experimental time points (T0 = day of explant; T7 = day 7; T10 = day 10; T14 = day 14); samples were then evaluated through immune, histological, and molecular analyses, cell morpho-functional characteristics; with particular focus on matrix composition and expression of vascular factors. It was observed that hypoxia retained the initial phenotype of cells and induced extracellular matrix production resembling a mature tissue. Hypoxia also modulated the expression of angiogenic factors, especially in the early phase of the study. Thus, we observed that hypoxia contributes to the fibro-chondrogenic differentiation with the involvement of angiogenic factors, especially in the posterior horn, which corresponds to the predominant weight-bearing portion.
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Aspriţoiu VM, Stoica I, Bleotu C, Diaconu CC. Epigenetic Regulation of Angiogenesis in Development and Tumors Progression: Potential Implications for Cancer Treatment. Front Cell Dev Biol 2021; 9:689962. [PMID: 34552922 PMCID: PMC8451900 DOI: 10.3389/fcell.2021.689962] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2021] [Accepted: 08/16/2021] [Indexed: 12/15/2022] Open
Abstract
Angiogenesis is a multi-stage process of new blood vessel development from pre-existing vessels toward an angiogenic stimulus. The process is essential for tissue maintenance and homeostasis during embryonic development and adult life as well as tumor growth. Under normal conditions, angiogenesis is involved in physiological processes, such as wound healing, cyclic regeneration of the endometrium, placental development and repairing certain cardiac damage, in pathological conditions, it is frequently associated with cancer development and metastasis. The control mechanisms of angiogenesis in carcinogenesis are tightly regulated at the genetic and epigenetic level. While genetic alterations are the critical part of gene silencing in cancer cells, epigenetic dysregulation can lead to repression of tumor suppressor genes or oncogene activation, becoming an important event in early development and the late stages of tumor development, as well. The global alteration of the epigenetic spectrum, which includes DNA methylation, histone modification, chromatin remodeling, microRNAs, and other chromatin components, is considered one of the hallmarks of cancer, and the efforts are concentrated on the discovery of molecular epigenetic markers that identify cancerous precursor lesions or early stage cancer. This review aims to highlight recent findings on the genetic and epigenetic changes that can occur in physiological and pathological angiogenesis and analyze current knowledge on how deregulation of epigenetic modifiers contributes to tumorigenesis and tumor maintenance. Also, we will evaluate the clinical relevance of epigenetic markers of angiogenesis and the potential use of "epi-drugs" in modulating the responsiveness of cancer cells to anticancer therapy through chemotherapy, radiotherapy, immunotherapy and hormone therapy as anti-angiogenic strategies in cancer.
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Affiliation(s)
| | - Ileana Stoica
- Faculty of Biology, University of Bucharest, Bucharest, Romania
| | - Coralia Bleotu
- Faculty of Biology, University of Bucharest, Bucharest, Romania
- Romanian Academy, Stefan S. Nicolau Institute of Virology, Bucharest, Romania
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Zhu H, Zhang Y, Zhong Y, Ye Y, Hu X, Gu L, Xiong X. Inflammation-Mediated Angiogenesis in Ischemic Stroke. Front Cell Neurosci 2021; 15:652647. [PMID: 33967696 PMCID: PMC8096981 DOI: 10.3389/fncel.2021.652647] [Citation(s) in RCA: 76] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2021] [Accepted: 02/16/2021] [Indexed: 12/12/2022] Open
Abstract
Stroke is the leading cause of disability and mortality in the world, but the pathogenesis of ischemic stroke (IS) is not completely clear and treatments are limited. Mounting evidence indicate that neovascularization is a critical defensive reaction to hypoxia that modulates the process of long-term neurologic recovery after IS. Angiogenesis is a complex process in which the original endothelial cells in blood vessels are differentiated, proliferated, migrated, and finally remolded into new blood vessels. Many immune cells and cytokines, as well as growth factors, are directly or indirectly involved in the regulation of angiogenesis. Inflammatory cells can affect endothelial cell proliferation, migration, and activation by secreting a variety of cytokines via various inflammation-relative signaling pathways and thus participate in the process of angiogenesis. However, the mechanism of inflammation-mediated angiogenesis has not been fully elucidated. Hence, this review aimed to discuss the mechanism of inflammation-mediated angiogenesis in IS and to provide new ideas for clinical treatment of IS.
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Affiliation(s)
- Hua Zhu
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, China.,Central Laboratory, Renmin Hospital of Wuhan University, Wuhan, China
| | - Yonggang Zhang
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, China.,Central Laboratory, Renmin Hospital of Wuhan University, Wuhan, China
| | - Yi Zhong
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, China
| | - Yingze Ye
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, China
| | - Xinyao Hu
- Department of Oncology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Lijuan Gu
- Central Laboratory, Renmin Hospital of Wuhan University, Wuhan, China.,Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Xiaoxing Xiong
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, China.,Central Laboratory, Renmin Hospital of Wuhan University, Wuhan, China
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Co-Culture of Primary Human Coronary Artery and Internal Thoracic Artery Endothelial Cells Results in Mutually Beneficial Paracrine Interactions. Int J Mol Sci 2020; 21:ijms21218032. [PMID: 33126651 PMCID: PMC7663246 DOI: 10.3390/ijms21218032] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2020] [Revised: 10/21/2020] [Accepted: 10/27/2020] [Indexed: 12/12/2022] Open
Abstract
Although saphenous veins (SVs) are commonly used as conduits for coronary artery bypass grafting (CABG), internal thoracic artery (ITA) grafts have significantly higher long-term patency. As SVs and ITA endothelial cells (ECs) have a considerable level of heterogeneity, we suggested that synergistic paracrine interactions between CA and ITA ECs (HCAECs and HITAECs, respectively) may explain the increased resistance of ITA grafts and adjacent CAs to atherosclerosis and restenosis. In this study, we measured the gene and protein expression of the molecules responsible for endothelial homeostasis, pro-inflammatory response, and endothelial-to-mesenchymal transition in HCAECs co-cultured with either HITAECs or SV ECs (HSaVECs) for an ascending duration. Upon the co-culture, HCAECs and HITAECs showed augmented expression of endothelial nitric oxide synthase (eNOS) and reduced expression of endothelial-to-mesenchymal transition transcription factors Snail and Slug when compared to the HCAEC–HSaVEC model. HCAECs co-cultured with HITAECs demonstrated an upregulation of HES1, a master regulator of arterial specification, of which the expression was also exclusively induced in HSaVECs co-cultured with HCAECs, suggestive of their arterialisation. In addition, co-culture of HCAECs and HITAECs promoted the release of pro-angiogenic molecules. To conclude, co-culture of HCAECs and HITAECs results in reciprocal and beneficial paracrine interactions that might contribute to the better performance of ITA grafts upon CABG.
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Mutgan AC, Jandl K, Kwapiszewska G. Endothelial Basement Membrane Components and Their Products, Matrikines: Active Drivers of Pulmonary Hypertension? Cells 2020; 9:cells9092029. [PMID: 32899187 PMCID: PMC7563239 DOI: 10.3390/cells9092029] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2020] [Revised: 08/27/2020] [Accepted: 08/29/2020] [Indexed: 12/19/2022] Open
Abstract
Pulmonary arterial hypertension (PAH) is a vascular disease that is characterized by elevated pulmonary arterial pressure (PAP) due to progressive vascular remodeling. Extracellular matrix (ECM) deposition in pulmonary arteries (PA) is one of the key features of vascular remodeling. Emerging evidence indicates that the basement membrane (BM), a specialized cluster of ECM proteins underlying the endothelium, may be actively involved in the progression of vascular remodeling. The BM and its steady turnover are pivotal for maintaining appropriate vascular functions. However, the pathologically elevated turnover of BM components leads to an increased release of biologically active short fragments, which are called matrikines. Both BM components and their matrikines can interfere with pivotal biological processes, such as survival, proliferation, adhesion, and migration and thus may actively contribute to endothelial dysfunction. Therefore, in this review, we summarize the emerging role of the BM and its matrikines on the vascular endothelium and further discuss its implications on lung vascular remodeling in pulmonary hypertension.
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Affiliation(s)
- Ayse Ceren Mutgan
- Otto Loewi Research Center, Division of Physiology, Medical University of Graz, 8010 Graz, Austria;
| | - Katharina Jandl
- Ludwig Boltzmann Institute for Lung Vascular Research, 8010 Graz, Austria;
- Otto Loewi Research Center, Division of Pharmacology, Medical University of Graz, 8010 Graz, Austria
| | - Grazyna Kwapiszewska
- Otto Loewi Research Center, Division of Physiology, Medical University of Graz, 8010 Graz, Austria;
- Ludwig Boltzmann Institute for Lung Vascular Research, 8010 Graz, Austria;
- Correspondence:
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9
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High levels of FLT3-ligand in bone marrow and peripheral blood of patients with advanced multiple myeloma. PLoS One 2017; 12:e0181487. [PMID: 28727816 PMCID: PMC5519162 DOI: 10.1371/journal.pone.0181487] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2017] [Accepted: 06/30/2017] [Indexed: 11/19/2022] Open
Abstract
Introduction Multiple myeloma (MM) is still incurable due to resistance against various therapies. Thus, the identification of biomarkers predicting progression is urgently needed. Here, we evaluated four biomarkers in bone marrow and peripheral blood of MM patients for their prognostic significance. Materials & methods Bone marrow- and peripheral blood plasma levels of FLT3-L, soluble TIE2, endostatin, and osteoactivin were determined in patients with monoclonal gammopathy of undetermined significance (MGUS, n = 14/n = 4), patients with newly diagnosed MM (NDMM, n = 42/n = 31) and patients with relapsed/refractory MM (RRMM, n = 27/n = 16) by sandwich ELISA. Results Median FLT3-L expression increased from MGUS (58.77 pg/ml in bone marrow; 80.40 pg/ml in peripheral blood) to NDMM (63.15 pg/ml in bone marrow; 85.05 pg/ml in peripheral blood) and was maximal in RRMM (122 pg/ml in bone marrow; 160.47 pg/ml in peripheral blood; NDMM vs. RRMM p<0.001). A cut-off value of FLT3-L >92 pg/ml in bone marrow and >121 pg/ml in peripheral blood was associated with relapse or refractoriness in MM patients. FLT3-L was found to be a high predictive marker for discrimination between NDMM and RRMM as well in bone marrow as in peripheral blood (AUC 0.75 in bone marrow; vs 0.84 in peripheral blood). Conclusion High levels of FLT3-L in bone marrow and peripheral blood of MM patients identify patients with progressive disease and are associated with relapse or refractoriness in MM patients. FLT3-L could be useful as a marker to identify RRMM patients and should be evaluated as target for future therapies.
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10
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Hirtenlehner K, Pollheimer J, Lichtenberger C, Wolschek MF, Zeisler H, Husslein P, Knöfler M. Elevated Serum Concentrations of the Angiogenesis Inhibitor Endostatin in Preeclamptic Women. ACTA ACUST UNITED AC 2016. [DOI: 10.1016/s1071-55760300142-4] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Affiliation(s)
| | | | | | | | | | - Peter Husslein
- Departments of Obstetrics and Gynecology and Internal Medicine IV, University of Vienna, Vienna, Austria
| | - Martin Knöfler
- Departments of Obstetrics and Gynecology and Internal Medicine IV, University of Vienna, Vienna, Austria; Department of Obstetrics and Gynecology, University of Vienna, AKH, Waehringer Guertel 18-20, A-1090 Vienna, Austria
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11
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Jana S, Tranquillo RT, Lerman A. Cells for tissue engineering of cardiac valves. J Tissue Eng Regen Med 2015; 10:804-824. [DOI: 10.1002/term.2010] [Citation(s) in RCA: 46] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2014] [Revised: 12/15/2014] [Accepted: 01/12/2015] [Indexed: 12/20/2022]
Affiliation(s)
- Soumen Jana
- Division of Cardiovascular Diseases; Mayo Clinic; Rochester MN USA
| | - Robert T. Tranquillo
- Department of Biomedical Engineering; University of Minnesota; Minneapolis MN USA
| | - Amir Lerman
- Division of Cardiovascular Diseases; Mayo Clinic; Rochester MN USA
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12
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Choi BH, Choi KH, Lee HS, Song BR, Park SR, Yang JW, Min BH. Inhibition of blood vessel formation by a chondrocyte-derived extracellular matrix. Biomaterials 2014; 35:5711-20. [PMID: 24768193 DOI: 10.1016/j.biomaterials.2014.03.083] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2014] [Accepted: 03/28/2014] [Indexed: 12/20/2022]
Abstract
In this study, the chondrocyte-derived extracellular matrix (CECM) was evaluated for its activity to inhibit vessel invasion in vitro and in vivo. Human umbilical vein endothelial cells (HUVECs) and rabbit chondrocytes were plated on a bio-membrane made of CECM or human amniotic membrane (HAM). The adhesion, proliferation, and tube formation activity of HUVECs and chondrocytes were examined. The CECM and HAM powders were then mixed individually in Matrigel and injected subcutaneously into nude mice to examine vessel invasion in vivo after 1 week. Finally, a rabbit model of corneal neovascularization (NV) was induced by 3-point sutures in the upper cornea, and CECM and HAM membranes were implanted onto the corneal surface at day 5 after suture injury. The rabbits were sacrificed at 7 days after transplantation and the histopathological analysis was performed. The adhesion and proliferation of HUVECs were more efficient on the HAM than on the CECM membrane. However, chondrocytes on each membrane showed an opposite result being more efficient on the CECM membrane. The vessel invasion in vivo also occurred more deeply and intensively in Matrigel containing HAM than in the one containing CECM. In the rabbit NV model, CECM efficiently inhibited the neovessels formation and histological remodeling in the injured cornea. In summary, our findings suggest that CECM, an integral cartilage ECM composite, shows an inhibitory effect on vessel invasion both in vitro and in vivo, and could be a useful tool in a variety of biological and therapeutic applications including the prevention of neovascularization after cornea injury.
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Affiliation(s)
- Byung Hyune Choi
- Department of Advanced Biomedical Sciences, College of Medicine, Inha University, Incheon, Republic of Korea
| | - Kyoung-Hwan Choi
- Department of Molecular Science and Technology, Ajou University, Suwon, Republic of Korea; Cell Therapy Center, Ajou Medical Center, Suwon, Republic of Korea
| | - Hye Sook Lee
- Ocular Neovascular Disease Research Center, Inje University Busan Paik Hospital, Busan, Republic of Korea
| | - Bo Ram Song
- Department of Molecular Science and Technology, Ajou University, Suwon, Republic of Korea; Cell Therapy Center, Ajou Medical Center, Suwon, Republic of Korea
| | - So Ra Park
- Department of Physiology, College of Medicine, Inha University, Incheon, Republic of Korea
| | - Jae Wook Yang
- Ocular Neovascular Disease Research Center, Inje University Busan Paik Hospital, Busan, Republic of Korea; Department of Ophthalmology, Inje University College of Medicine, Busan Paik Hospital, Busan, Republic of Korea.
| | - Byoung-Hyun Min
- Department of Molecular Science and Technology, Ajou University, Suwon, Republic of Korea; Cell Therapy Center, Ajou Medical Center, Suwon, Republic of Korea; Department of Orthopedic Surgery, School of Medicine, Ajou University, Suwon, Republic of Korea.
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13
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Zacharoulis D, Hatzitheofilou C, Athanasiou E, Zacharoulis S. Antiangiogenic strategies in hepatocellular carcinoma: current status. Expert Rev Anticancer Ther 2014; 5:645-56. [PMID: 16111465 DOI: 10.1586/14737140.5.4.645] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Hepatocellular carcinoma is a leading cause of cancer death worldwide in both adult and pediatric patients. Despite many options, no ideal treatment exists for this highly malignant tumor, and management strategies have varied accordingly. Angiogenesis, the formation of new blood vessels, is an essential component of hepatocellular carcinoma biology. Innovative approaches such as targeting the nontransformed, less resistant, tumor-supporting endothelial cells are currently under investigation in hepatocellular carcinoma. This review will focus on the current knowledge of the pathophysiology of hepatocellular carcinoma angiogenesis, as well as the reported data with angiogenesis inhibitors against hepatocellular carcinoma.
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14
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CKD-516 displays vascular disrupting properties and enhances anti-tumor activity in combination with chemotherapy in a murine tumor model. Invest New Drugs 2013; 32:400-11. [PMID: 24202729 DOI: 10.1007/s10637-013-0043-8] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2013] [Accepted: 10/17/2013] [Indexed: 01/31/2023]
Abstract
PURPOSE CKD-516 is a benzophenone analog in which the B ring is modified by replacement with a carbonyl group. The study assessed CKD-516 as a vascular disrupting agent or anti-cancer drug. METHODS To assess the effect of S516 on vascularization, we analyzed the effect on human umbilical vein endothelial cells (HUVECs). To determine the inhibition of cell proliferation of S516, we used H460 lung carcinoma cells. The alteration of microtubules was analyzed using immunoblot, RT-PCR and confocal imaging. To evaluate the anti-tumor effects of gemcitabine and/or CKD-516, H460 xenograft mice were treated with CKD-516 (2.5 mg/kg) and/or gemcitabine (40 mg/kg), and tumor growth was compared with vehicle-treated control. For histologic analysis, liver, spleen and tumor tissues from H460 xenograft mice were obtained 12 and 24 h after CKD-516 injection. RESULTS Cytoskeletal changes of HUVECs treated with 10 nM S516 were assessed by immunoblot and confocal imaging. S516 disrupted tubulin assembly and resulted in microtubule dysfunction, which induced cell cycle arrest (G2/M). S516 markedly enhanced the depolymerization of microtubules, perhaps due to the vascular disrupting properties of S516. Interestingly, S516 decreased the amount of total tubulin protein in HUVECs. Especially, S516 decreased mRNA expression α-tubulin (HUVECs only) and β-tubulin (HUVECs and H460 cells) at an early time point (4 h). Immunocytochemical analysis showed that S516 changed the cellular microtubule network and inhibited the formation of polymerized microtubules. Extensive central necrosis of tumors was evident by 12 h after treatment with CKD-516 (2.5 mg/kg, i.p.). In H460 xenografts, CKD-516 combined with gemcitabine significantly delayed tumor growth up to 57 % and 36 % as compared to control and gemcitabine alone, respectively. CONCLUSION CKD-516 is a novel agent with vascular disrupting properties and enhances anti-tumor activity in combination with chemotherapy.
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HONG SANGWON, JUNG KYUNGHEE, CHOI MYUNGJOO, KIM DAYOUNG, LEE HEESEUNG, ZHENG HONGMEI, LI GUANGYONG, EL-DEEB IBRAHIMM, PARK BYUNGSUN, LEE SOHA, HONG SOONSUN. Anticancer effects of KI-10F: A novel compound affecting apoptosis, angiogenesis and cell growth in colon cancer. Int J Oncol 2012; 41:1715-22. [DOI: 10.3892/ijo.2012.1609] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2012] [Accepted: 07/27/2012] [Indexed: 11/05/2022] Open
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Pericytes on the tumor vasculature: jekyll or hyde? CANCER MICROENVIRONMENT 2012; 6:1-17. [PMID: 22467426 DOI: 10.1007/s12307-012-0102-2] [Citation(s) in RCA: 67] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/25/2012] [Accepted: 03/08/2012] [Indexed: 12/15/2022]
Abstract
The induction of tumor vasculature, known as the 'angiogenic switch', is a rate-limiting step in tumor progression. Normal blood vessels are composed of two distinct cell types: endothelial cells which form the channel through which blood flows, and mural cells, the pericytes and smooth muscle cells which serve to support and stabilize the endothelium. Most functional studies have focused on the responses of endothelial cells to pro-angiogenic stimuli; however, there is mounting evidence that the supporting mural cells, particularly pericytes, may play key regulatory roles in both promoting vessel growth as well as terminating vessel growth to generate a mature, quiescent vasculature. Tumor vessels are characterized by numerous structural and functional abnormalities, including altered association between endothelial cells and pericytes. These dysfunctional, unstable vessels contribute to hypoxia, interstitial fluid pressure, and enhanced susceptibility to metastatic invasion. Increasing evidence points to the pericyte as a critical regulator of endothelial activation and subsequent vessel development, stability, and function. Here we discuss both the stimulatory and inhibitory effects of pericytes on the vasculature and the possible utilization of vessel normalization as a therapeutic strategy to combat cancer.
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Weisshardt P, Trarbach T, Dürig J, Paul A, Reis H, Tilki D, Miroschnik I, Ergün S, Klein D. Tumor vessel stabilization and remodeling by anti-angiogenic therapy with bevacizumab. Histochem Cell Biol 2011; 137:391-401. [PMID: 22193946 DOI: 10.1007/s00418-011-0898-8] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/29/2011] [Indexed: 12/12/2022]
Abstract
Bevacizumab-resistant tumor vessels were characterized by an increased vessel diameter and normalization of vascular structures by the recruitment of mature pericytes and smooth muscle cells. Here, we analyzed human liver metastases which were taken at clinical relapse in patients with colorectal adenocarcinoma treated with anti-angiogenic therapy using the humanized monoclonal anti-VEGF bevacizumab. Tumor vessels which are resistant to anti-VEGF therapy are increased in size and characterized by a normalization of the vascular bed. These results were confirmed using NOD SCID mice as animal model and xenograft transplantation of human PC-3 prostate carcinoma cells in combination with bevacizumab treatment. Our results confirmed that anti-angiogenic therapy results in enhanced vascular remodeling by vascular stabilization. This process is apparently accompanied by enhanced necrosis of tumor tissue. These processes interfere with the efficacy of anti-angiogenic therapy because of reduced susceptibility of stabilized vessels by this therapy. These results demonstrate the importance for the development of second generation anti-angiogenic combination therapy concepts to rule out the balance between vascular stabilization followed by a possible de-stabilization making the remained vessels susceptible to a second wave of anti-angiogenic therapy.
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Affiliation(s)
- Philip Weisshardt
- Institute of Anatomy, University Hospital Essen, University of Duisburg-Essen, Hufelandstrasse 55, 45147 Essen, Germany.
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Szarvas T, László V, Vom Dorp F, Reis H, Szendröi A, Romics I, Tilki D, Rübben H, Ergün S. Serum endostatin levels correlate with enhanced extracellular matrix degradation and poor patients' prognosis in bladder cancer. Int J Cancer 2011; 130:2922-9. [PMID: 21815140 DOI: 10.1002/ijc.26343] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2011] [Accepted: 07/20/2011] [Indexed: 01/13/2023]
Abstract
Endostatin, the proteolytic fragment of collagen XVIII, is an inhibitor of angiogenesis and tumor growth. Interestingly, elevated circulating endostatin levels have been found to correlate with poor patients' prognosis in several cancers. The aim of this study was to assess the prognostic value of endostatin in bladder cancer (BC) and to gain insight into the mechanisms involved in its production. This retrospective study included a total of 337 patients with BC and 103 controls. Collagen XVIII gene expression was analyzed using real-time PCR (n = 82). Endostatin tissue localization was assessed by immunohistochemistry (n = 27). Endostatin serum (n = 87) and urine (n = 153) levels were determined by ELISA. In 12 cases, both serum and paraffinized tissue samples from the same patients were available. We found decreased collagen XVIII tissue expression and increased endostatin urine and serum concentration in samples of patients with BC compared to controls. High serum endostatin levels correlated with the presence of lymph node metastases and MMP-7 concentrations and were independently associated with poor metastasis-free and disease-specific survival. Immunohistochemical analysis revealed a strong endostatin staining in the wall of tumor associated blood vessels in superficial but not in muscle-invasive BCs. Based on these, we concluded that elevated endostatin levels in patients with BC are the consequence of enhanced extracellular matrix degradation and are independent from collagen XVIII expression. Furthermore, serum endostatin levels may provide prognostic information independent from histopathological parameters and may therefore help to optimize therapy decisions. Loss of endostatin expression in tumor associated blood vessels might represent an important step supporting tumor-induced angiogenesis.
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Affiliation(s)
- Tibor Szarvas
- Department of Urology, University of Duisburg-Essen, Germany.
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Abstract
Epidemiologic results tend to suggest that adults with Down syndrome have a reduced incidence of cancer, but some studies have reached the opposite conclusion. In this study, we offer direct biological evidence in support of the notion that Down syndrome reduces incidence of multiple types of cancer. Previous studies showed that introduction of the Apc(Min) mutation into the Ts65Dn mouse model of Down syndrome by interbreeding caused formation of intestinal adenomas at a significantly reduced incidence compared with control (euploid) animals that did not have trisomy. To a large degree, this reduction was determined to reflect an increased dosage of the Ets2 tumor repressor gene due to trisomy. Studies of tumor grafts using Ts65Dn suggested angiogenesis as a mechanism that mediated reduced tumor growth, metastasis, and mortality in individuals with Down syndrome. To confirm and extend these findings, we employed the complex cancer mouse model NPcis, which is heterozygous for the Trp53 and Nf1 genes and through LOH develops lymphomas, sarcomas, or carcinomas with 100% penetrance. In this aggressive model, trisomy did not prevent cancer, but it nevertheless extended host survival relative to euploid littermates. However, protection in this case was not attributable to either Ets2 dosage or to reduced angiogenesis. Together, our findings indicate that the genetic complexity underlying Down syndrome supports multiple mechanisms that contribute to reduced mortality from cancer.
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Affiliation(s)
- Annan Yang
- Department of Physiology and McKusick Nathans Institute for Genetic Medicine, School of Medicine, Johns Hopkins University, Baltimore, MD 21205
| | - Roger H. Reeves
- Department of Physiology and McKusick Nathans Institute for Genetic Medicine, School of Medicine, Johns Hopkins University, Baltimore, MD 21205
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Seppinen L, Pihlajaniemi T. The multiple functions of collagen XVIII in development and disease. Matrix Biol 2011; 30:83-92. [DOI: 10.1016/j.matbio.2010.11.001] [Citation(s) in RCA: 73] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2010] [Revised: 11/19/2010] [Accepted: 11/22/2010] [Indexed: 12/11/2022]
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Prakash SK, LeMaire SA, Guo DC, Russell L, Regalado ES, Golabbakhsh H, Johnson RJ, Safi HJ, Estrera AL, Coselli JS, Bray MS, Leal SM, Milewicz DM, Belmont JW. Rare copy number variants disrupt genes regulating vascular smooth muscle cell adhesion and contractility in sporadic thoracic aortic aneurysms and dissections. Am J Hum Genet 2010; 87:743-56. [PMID: 21092924 DOI: 10.1016/j.ajhg.2010.09.015] [Citation(s) in RCA: 66] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2010] [Revised: 09/07/2010] [Accepted: 09/16/2010] [Indexed: 10/18/2022] Open
Abstract
Thoracic aortic aneurysms and dissections (TAAD) cause significant morbidity and mortality, but the genetic origins of TAAD remain largely unknown. In a genome-wide analysis of 418 sporadic TAAD cases, we identified 47 copy number variant (CNV) regions that were enriched in or unique to TAAD patients compared to population controls. Gene ontology, expression profiling, and network analysis showed that genes within TAAD CNVs regulate smooth muscle cell adhesion or contractility and interact with the smooth muscle-specific isoforms of α-actin and β-myosin, which are known to cause familial TAAD when altered. Enrichment of these gene functions in rare CNVs was replicated in independent cohorts with sporadic TAAD (STAAD, n = 387) and inherited TAAD (FTAAD, n = 88). The overall prevalence of rare CNVs (23%) was significantly increased in FTAAD compared with STAAD patients (Fisher's exact test, p = 0.03). Our findings suggest that rare CNVs disrupting smooth muscle adhesion or contraction contribute to both sporadic and familial disease.
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Babiker AA, Magnusson PU, Ronquist G, Nilsson B, Ekdahl KN. Mapping pro- and antiangiogenic factors on the surface of prostasomes of normal and malignant cell origin. Prostate 2010; 70:834-47. [PMID: 20127731 DOI: 10.1002/pros.21117] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
Abstract
BACKGROUND Angiogenesis is the formation of new blood vessels by capillary sprouting from pre-existing vessels. Tumor growth is angiogenesis-dependent and the formation of new blood vessels is associated with the increased expression of angiogenic factors. Prostasomes are secretory granules produced, stored and released by the glandular epithelial cells of the prostate. We investigated the expression of selected angiogenic and anti-angiogenic factors on the surface of prostasomes of different origins as well as the direct effect of prostasomes on angiogenesis. METHODS VEGF, endothelin-1, endostatin, and thrombospondin-1 were determined on prostasomes from seminal fluid and human prostate cancer cell lines (DU145,PC-3,LNCaP) using different immunochemical techniques. Human dermal microvascular endothelial cells were incubated with seminal and DU145 cell-prostasomes and with radioactive thymidine. The effect of prostasomes on angiogenesis was judged by measuring the uptake of labeled thymidine. The presence of any deleterious effects of prostasomes on the endothelial cells was investigated using thymidine assay and confocal laser microscopy. RESULTS VEGF and endothelin-1 were determined on malignant cell-prostasomes (no difference between cell lines) but not determined on seminal prostasomes. The same applies for the expression of endostatin but with much higher expression on malignant cell-prostasomes with obvious differences between them. Seminal and DU145 cell-prostasomes were found to have anti-angiogenic effect which was more expressed by DU145 cell-prostasomes. No deleterious effect of prostasomes on endothelial function was detected using either thymidine assay or microscopy. CONCLUSIONS Prostasomes contain pro- and anti-angiogenic factors that function to counteract each other unless the impact from one side exceeds the other to bring about dysequilibrium.
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Affiliation(s)
- Adil A Babiker
- Rudbeck Laboratory C5, Department of Oncology, Uppsala, Sweden
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Emerging biology of vascular wall progenitor cells in health and disease. Trends Mol Med 2009; 15:501-9. [PMID: 19828379 DOI: 10.1016/j.molmed.2009.09.004] [Citation(s) in RCA: 50] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2009] [Revised: 08/25/2009] [Accepted: 09/04/2009] [Indexed: 01/04/2023]
Abstract
New blood vessels are formed through angiogenesis and postnatal vasculogenesis. Thus, it is essential to identify vascular stem and progenitor cell niches and the mechanisms governing their role in blood vessel formation. Although much is known about circulating and bone marrow-derived endothelial progenitor cells (EPCs), little is known about the vascular wall as an EPC niche. Experimental evidence strongly suggests that EPCs, as well as other stem and progenitor cells, reside in distinct zones of the vessel wall, such as within the subendothelial space and in the so-called "vasculogenic zone" within the vascular adventitia. In this review, we discuss the potential implications of different types of vascular wall resident stem and progenitor cells in health and disease.
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Wikström AK, Larsson A, Åkerud H, Olovsson M. Increased Circulating Levels of the Antiangiogenic Factor Endostatin in Early-Onset But Not Late-Onset Preeclampsia. Reprod Sci 2009; 16:995-1000. [DOI: 10.1177/1933719109339348] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Affiliation(s)
- Anna-Karin Wikström
- Department of Women's and Children's Health, Uppsala University, Uppsala, Sweden,
| | - Anders Larsson
- Department of Medical Sciences, Uppsala University, Uppsala, Sweden
| | - Helena Åkerud
- Department of Women's and Children's Health, Uppsala University, Uppsala, Sweden
| | - Matts Olovsson
- Department of Women's and Children's Health, Uppsala University, Uppsala, Sweden
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Neskey DM, Ambesi A, Pumiglia KM, McKeown-Longo PJ. Endostatin and anastellin inhibit distinct aspects of the angiogenic process. J Exp Clin Cancer Res 2008; 27:61. [PMID: 18983664 PMCID: PMC2584004 DOI: 10.1186/1756-9966-27-61] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2008] [Accepted: 11/04/2008] [Indexed: 01/14/2023] Open
Abstract
BACKGROUND Endostatin and anastellin, fragments of collagen type XVIII and fibronectin, respectively, belong to a family of endogenous inhibitors of angiogenesis which inhibit tumor growth and metastasis in a number of mouse models of human cancer. The mechanism of action of these inhibitors is not well understood, but they have great potential usefulness as non-toxic long-term therapy for cancer treatment. METHODS In this study, we compare the anti-angiogenic properties of endostatin and anastellin using cell proliferation and transwell migration assays. RESULTS Anastellin but not endostatin completely inhibited human dermal microvessel endothelial cell proliferation in response to serum stimulation. Both anastellin and endostatin additively inhibited endothelial cell migration in response to VEGF. Anastellin but not endostatin lowered basal levels of active ERK. CONCLUSION These data indicate that anastellin and endostatin exert their anti-angiogenic effects by modulating distinct steps in the angiogenic pathway and suggest that matrix-derived inhibitors of angiogenesis may exhibit higher efficacy when used in combination.
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Affiliation(s)
- David M Neskey
- Center for Cell Biology & Cancer Research, Albany Medical College, Albany, New York 12208, USA
| | - Anthony Ambesi
- Center for Cell Biology & Cancer Research, Albany Medical College, Albany, New York 12208, USA
| | - Kevin M Pumiglia
- Center for Cell Biology & Cancer Research, Albany Medical College, Albany, New York 12208, USA
| | - Paula J McKeown-Longo
- Center for Cell Biology & Cancer Research, Albany Medical College, Albany, New York 12208, USA
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Tatar O, Shinoda K, Kaiserling E, Claes C, Eckardt C, Eckert T, Pertile G, Boeyden V, Scharioth GB, Yoeruek E, Szurman P, Bartz-Schmidt KU, Grisanti S. Implications of bevacizumab on vascular endothelial growth factor and endostatin in human choroidal neovascularisation. Br J Ophthalmol 2008; 93:159-65. [PMID: 18838410 DOI: 10.1136/bjo.2008.138594] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Abstract
AIM To evaluate the implications of intravitreal bevacizumab on proangiogenic vascular endothelial growth factor (VEGF) with regard to the endogenous angiogenesis inhibitor endostatin in human choroidal neovascularisation (CNV) secondary to age-related macular degeneration. METHODS Retrospective review of an interventional case series of 48 patients who underwent full macular translocation surgery with removal of CNV. Twenty-five patients were treated with intravitreal bevacizumab injection 1 to 154 days prior to surgery (bevacizumab CNV). Twenty-three CNV without any kind of previous treatment were used as controls (control CNV). CNV were stained for CD34, cytokeratin18, VEGF, endostatin and E-selectin. A "predominance score of VEGF over endostatin" (PS) was defined by the difference between VEGF and endostatin staining scores. RESULTS Bevacizumab CNV revealed a weaker VEGF expression in endothelial cells (p = 0.0245) but significantly more intense endostatin in retina pigment epithelium (RPE) (p = 0.0001) and stroma (p<0.0001). Consequently, PS was significantly lower in RPE (p = 0.02), vessels (p = 0.03) and stroma (p = 0.0004) in bevacizumab CNV. The intensity of E-selectin expression in bevacizumab CNV was comparable with that in control CNV. CONCLUSIONS A shift within the angiogenic balance in terms of decreased VEGF predominance over endostatin is detected in human CNV treated with bevacizumab.
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Affiliation(s)
- O Tatar
- University Eye Clinic at the Centre for Ophthalmology, Eberhard-Karls-University, Tuebingen, Germany
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Grisanti S, Tatar O. The role of vascular endothelial growth factor and other endogenous interplayers in age-related macular degeneration. Prog Retin Eye Res 2008; 27:372-90. [PMID: 18621565 DOI: 10.1016/j.preteyeres.2008.05.002] [Citation(s) in RCA: 115] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Age-related macular degeneration (AMD) is a multifaceted disease characterized by early subclinical changes at the choroidea-retinal pigment epithelium interface. Both the causal and formal pathogenesis of the disease is still puzzling. Similarly, the reason for progression into two distinct late forms which are "geographic atrophy" and "choroidal neovascularization" remains enigmatic. Late changes are usually responsible for the dramatic loss in central function that has a devastating effect on quality of life. In industrialized countries the disease is a major cause for visual disability among persons over 60 years of age. Due to demographic right-shift and increased life expectancy, AMD is not only a medical problem but will have a pronounced socio-economic effect. Neovascular AMD with the development of choroidal neovascularization in the macular area accounts for 80% of the severe loss of visual acuity due to AMD. In the last decades, treatment modes were merely based on the destruction or surgical removal of the neovascular complex. In the present, however, the philosophical approach to treat the disease is changing to a pathology modifying manner. Intelligent targeting of the involved relevant factors and pathways should stop disease progression, reduce complications and improve vision. The first step into this new era has been accomplished with the introduction of antiangiogenic agents. The new agents act either directly on vascular endothelial growth factor (VEGF) or indirectly on its functional cascade. VEGF makes a fundamental contribution to neovascular processes but it also acts in physiological pathways. The main purpose of this review is to summarize its physiological role especially within the eye, the role in the development of AMD and to understand and foresee both the benefits and potential side-effects of the anti-VEGF-based therapy.
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Affiliation(s)
- Salvatore Grisanti
- Department of Ophthalmology at the University of Luebeck, Ratzeburger Allee 160, 23538 Luebeck, Germany.
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Tilki D, Kilic N, Herbst H, Reich O, Seitz M, Lauke H, Stief CG, Ergün S. High level of endostatin in epididymal epithelium: protection against primary malignancies in this organ? Histochem Cell Biol 2008; 130:527-35. [PMID: 18478248 DOI: 10.1007/s00418-008-0440-9] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/05/2008] [Indexed: 12/11/2022]
Abstract
Rete testis and epididymis are rare locations for primary tumors or metastasis. Assuming that this may be related to expression level of angiogenic inhibitors, we focused our study on the expression pattern of collagen 18/endostatin. In situ hybridization and immunohistochemistry for collagen 18 and endostatin were carried out on sections of human rete testis and epididymis as well as on epididymal adenoma and human testicular tissue with or without carcinoma in situ (CIS). In situ hybridization revealed strong expression of collagen 18 mRNA in rete testis, efferent ducts and epididymal duct. Immunostaining showed collagen 18 in epithelium and basement membrane as well as in blood vessels of rete testis. Further, in both efferent ducts and epididymal duct, collagen 18 was mainly localized in the basement membrane of these ducts and of the blood vessel wall. Endostatin immunostaining was localized in the epithelium of rete testis, efferent ducts and epididymal duct. This pattern of endostatin staining was absent in epididymal adenoma tissue while tumor associated blood vessels exhibited strong endostatin staining. No endostatin staining was detectable in normal germinal epithelium and CIS cells while Leydig cells exhibited strong endostatin staining. High endostatin expression in epididymis may protect this organ against tumor development. Gene therapeutic strategies providing high expression of endostatin in normal epithelia may be useful to prevent tumor development.
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Affiliation(s)
- Derya Tilki
- Department of Urology, University Hospital Grosshadern-Munich, Marchioninistr. 15, 81377 Munich, Germany.
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Tilki D, Singer B, Seitz M, Stief CG, Ergün S. [Molecular imaging of tumor blood vessels]. Urologe A 2008; 46:1266-71. [PMID: 17639291 DOI: 10.1007/s00120-007-1516-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
In the past three decades many efforts have been undertaken to understand the mechanisms of tumor angiogenesis. The introduction of the anti-angiogenic drugs in tumor therapy during the last few years necessitates the establishment of new techniques enabling molecular imaging of vascular remodeling. Tumor imaging by X-ray, CT, MRI and ultrasound has to be improved by coupling with molecular markers targeting the tumor vessels. The determination of tumor size as commonly used is not appropriate since the extended necrosis under anti-angiogenic therapy does not result in a reduction of tumor diameter. But remodeling of the tumor vessels under anti-angiogenic therapy obviously occurs at an early stage and seems to be a convincing parameter for tumor imaging. Despite the enormous progress in this field during the last few years the resolution is still not high enough to evaluate the remodeling of the microtumor vessels. Thus, new imaging approaches are needed to overcome this issue.
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Affiliation(s)
- D Tilki
- Urologische Klinik und Poliklinik, Klinikum der Ludwig-Maximilians-Universität, München
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Seppinen L, Sormunen R, Soini Y, Elamaa H, Heljasvaara R, Pihlajaniemi T. Lack of collagen XVIII accelerates cutaneous wound healing, while overexpression of its endostatin domain leads to delayed healing. Matrix Biol 2008; 27:535-46. [PMID: 18455382 DOI: 10.1016/j.matbio.2008.03.003] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2007] [Revised: 03/11/2008] [Accepted: 03/14/2008] [Indexed: 11/25/2022]
Abstract
Endostatin, the C-terminal fragment of collagen XVIII, is known to suppress tumour growth and angiogenesis by inhibiting endothelial cell proliferation and migration. We have previously shown that endostatin and its precursor are important for the structural organization of basement membranes (BM). The aim of this study was to investigate cutaneous wound healing in mice overexpressing endostatin in keratinocytes (ES-tg) and in mice lacking collagen XVIII (Col18a1(-/-)). Excisional wounds were made on the dorsal skin of mice, the wound areas were measured and the wounds were collected for further analyses after 3, 6 or 14 days. The healing of the wounds was delayed in the ES-tg mice and accelerated in the Col18a1(-/-) mice, and the vascularisation rate was accelerated in the Col18a1(-/-) mice, but not affected in the ES-tg mice. Abnormal capillaries with swollen endothelial cells and narrowed lumens were observed in the wounds of the ES-tg mice. In these mice also the formation of the epidermal BM was delayed, and the structure of the epidermal and capillary BMs was more disorganised. Moreover, detachment of the epidermis from the granulation tissue was observed in half (n=10) of the 6-day-old ES-tg wounds, but in none of the controls, suggesting an increased fragility of the epidermal-dermal junction in the presence of an excess of endostatin.
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Affiliation(s)
- Lotta Seppinen
- Biocenter Oulu, Collagen Research Unit, University of Oulu, Oulu, Finland
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Tilki D, Kilic N, Sevinc S, Zywietz F, Stief CG, Ergun S. Zone-specific remodeling of tumor blood vessels affects tumor growth. Cancer 2008; 110:2347-62. [PMID: 17849463 DOI: 10.1002/cncr.23024] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Chaotic organization, abnormal leakiness, and structural instability are characteristics of tumor vessels. However, morphologic events of vascular remodeling in relation to tumor growth are not sufficiently studied yet. METHODS By using the rat rhabdomyosarcoma tumor model vascular morphogenesis was studied by light and electron microscopy and immunohistochemistry in relation to tumor regions such as tumor surrounding (TSZ), marginal (TMZ), intermediate (TIZ), and center (TCZ) zones. RESULTS The analyses revealed that blood vessels of TSZ display a regular ultrastructure, whereas blood vessels of TMZ showed a chaotic organization and unstable structure with a diffuse or even lacking basal lamina, and missing or irregular assembled periendothelial cells. In contrast, blood vessels of TIZ and TCZ exhibited a more or less stabilized vessel structure with increased diameter. Correspondingly, normal assembly of alpha-smooth-muscle-actin (alpha-SMA)-positive cells into the vessel wall was observed in blood vessels of TSZ, TIZ, and TCZ. Also, Ang1 immunostaining was strongest in large vessels of TIZ and TCZ, whereas Ang2 staining was prominent in small vessels of TIZ. Tie2 staining was detectable in small and large vessels of all tumor zones. Immunostaining for alpha(v)beta(3)-integrin was strongest in small vessels of TMZ, whereas large vessels of TIZ and TCZ were almost negative. CONCLUSIONS The results indicate a zone-specific remodeling of tumor blood vessels by stabilization of vessels in TIZ and TCZ, whereas small vessels of these zones obviously undergo regression leading to tumor necrosis. Thus, a better understanding of vascular remodeling and stabilization in tumors would enable new strategies in tumor therapy and imaging.
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Affiliation(s)
- Derya Tilki
- Department of Urology, University Hospital Grosshadern, Munich, Germany
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Abstract
In 1998, George Vande Woude's lab discovered that anthrax lethal factor (LF), the principal virulence component of anthrax toxin, was a zinc-metalloprotease that cleaved and inactivated mitogen-activated protein kinase kinases (MKK). It was perhaps not surprising, given the known roles of MKK1 and 2 in cell proliferation, that LF was subsequently found to dramatically inhibit tumor growth in vivo. What was not anticipated, however, was that the tumors treated with LF would have a substantially reduced vascular content. This intriguing result was one of the first indications that MKK signaling plays an important role in promoting tumor vascularization in vivo. In the following short review, we will compare in vitro and in vivo evidence that supports the hypothesis that MKK signaling pathways are essential for vascularization.
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Affiliation(s)
- P E Depeille
- Laboratory of Cancer and Developmental Cell Biology, Van Andel Research Institute, 333 Bostwick Avenue, Grand Rapids, MI 49503, USA
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Tatar O, Shinoda K, Adam A, Eckert T, Eckardt C, Lucke K, Deuter C, Bartz-Schmidt KU, Grisanti S. Effect of verteporfin photodynamic therapy on endostatin and angiogenesis in human choroidal neovascular membranes. Br J Ophthalmol 2006; 91:166-73. [PMID: 16987895 PMCID: PMC1857619 DOI: 10.1136/bjo.2006.105288] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
AIM To evaluate the effect of verteporfin photodynamic therapy (PDT) on endostatin with regard to expression of vascular endothelial growth factor (VEGF) in human choroidal neovascular membranes (CNVs) secondary to age-related macular degeneration. METHODS A retrospective review of an interventional case series of 68 patients who underwent removal of CNV. 29 patients were treated with PDT 3-655 days before surgery. 39 CNVs without previous treatment were used as controls. CNVs were stained for CD34, CD105, Ki-67, cytokeratin 18, endostatin, E-selectin and VEGF. "Predominance score of VEGF over endostatin" (mean) was defined as the difference between VEGF and endostatin staining scores. RESULTS In four CNVs treated by PDT 3 days previously, PS was significantly higher in the retinal pigment epithelium (mean = 2.5, p = 0.006) and stroma (mean = 2, p = 0.015) than in the control group (mean = 0). At longer post-PDT intervals, PS was significantly decreased in the retinal pigment epithelium (mean = 0, p = 0.019) and stroma (mean = 0, p = 0.015). Proliferative activity was high (p = 0.023), but mostly related to inflammatory cells. PDT did not influence E-selectin expression significantly. CONCLUSIONS VEGF predominance over endostatin early after PDT might contribute to enhanced angiogenic activity associated with recurrences. Strategies upregulating or replacing endostatin early after PDT might increase the effectiveness of PDT.
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Affiliation(s)
- Olcay Tatar
- University Eye Hospital, Centre for Ophthalmology of Eberhard-Karls University, Schleichstrasse 12-15, 72076 Tuebingen, Germany
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Tatar O, Shinoda K, Adam A, Rohrbach JM, Lucke K, Henke-Fahle S, Bartz-Schmidt KU, Grisanti S. Expression of endostatin in human choroidal neovascular membranes secondary to age-related macular degeneration. Exp Eye Res 2006; 83:329-38. [PMID: 16584730 DOI: 10.1016/j.exer.2005.12.017] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2005] [Revised: 10/12/2005] [Accepted: 12/21/2005] [Indexed: 11/16/2022]
Abstract
Endostatin is an endogenous angiogenesis inhibitor which requires E-selectin for its antiangiogenic activity. The aim of this study was to investigate the expression of endostatin in human choroidal neovascular membranes (CNV) secondary to age-related macular degeneration (AMD) with regard to vascularization and proliferative activity. An interventional case series of 36 patients who underwent removal of CNV were retrospectively investigated. Thirty-six CNV were analyzed by light microscopic immunohistochemistry for the expression of CD34 (endothelial cells, EC), CD105 (activated EC), Ki-67 (cell proliferation), Cytokeratin 18 (epithelial cells), VEGF (vascular endothelial growth factor), E-selectin and endostatin. Donor eyes (n=7) including one with AMD were used as controls. Endostatin immunoreactivity was present in choroidal vessels of five as well as in the retinal pigment epithelium (RPE)-Bruch's membrane complex of two donor eyes without AMD. In one eye with AMD, endostatin was detected in RPE, Bruch's membrane and choroidal vessels. Ninety-two percent (33/36) of CNV disclosed endostatin staining. RPE-Bruch's membrane complex, choroidal vessels and stroma were positive in 50% (18/36), 72% (26/36), and 78% (28/36) of the membranes, respectively. Both control eyes and CNV expressed all the investigated markers except E-selectin being positive only in membranes. Endostatin, an endogenous angiogenesis inhibitor, is expressed in CNV and its therapeutic up-regulation may be a new strategy in the treatment of neovascular AMD.
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Affiliation(s)
- Olcay Tatar
- University Eye Clinic at the Centre for Ophthalmology of the Eberhard-Karls-University Tübingen, Schleichstrasse 12-15, 72076 Tuebingen, Germany
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Ergun S, Tilki D, Oliveira-Ferrer L, Schuch G, Kilic N. Significance of vascular stabilization for tumor growth and metastasis. Cancer Lett 2006; 238:180-7. [PMID: 16084013 DOI: 10.1016/j.canlet.2005.06.033] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2005] [Accepted: 06/23/2005] [Indexed: 11/19/2022]
Abstract
This mini review highlights the role of vascular stabilization which is apparently mediated by factors belonging to both the pro- and anti-angiogenic group. Knowingly angiopoietin-1 has pro-angiogenic properties while endostatin acts anti-angiogenic. But both factors suppress tumor growth in experimental tumor models. The crossing points of mechanisms of their action are the parameters vascular stabilization and vascular permeability, which are of high importance not only for tumor vascularization, but also for tissue vascularization in general. Both angiopoietin-1 and endostatin reduce the vascular permeability, but promote vascular stabilization. Vascular stabilization is significantly increased under experimental treatment of tumors with angiogenesis inhibitors such as endostatin. It inhibits tumor growth and probably tumor metastasis. The understanding of temporal and spatial sequences of vascular stabilization is an important challenge for scientists working on tumor vascularization and anti-angiogenic tumor therapy.
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Affiliation(s)
- Suleyman Ergun
- Center of Experimental Medicine, Institute of Anatomy I, University Hospital Hamburg-Eppendorf, Martinistr. 52, D-20246 Hamburg, Germany.
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Calfa CI, Rosenblatt JD, Cho HM, Webster K, Shin SU. Antibodies and antibody-fusion proteins as anti-angiogenic, anti-tumor agents. ACTA ACUST UNITED AC 2006. [DOI: 10.1016/j.uct.2006.05.001] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
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Li W, Li CB. Effect of oral Lactococcus lactis containing endostatin on 1, 2-dimethylhydrazine-induced colon tumor in rats. World J Gastroenterol 2006; 11:7242-7. [PMID: 16437622 PMCID: PMC4725132 DOI: 10.3748/wjg.v11.i46.7242] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate the effects of oral Lactococcus lactis (L lactis) containing endostatin on 1, 2-dimethylhydrazine (DMH)-induced rat colorectal cancer. METHODS Recombinant endostatin was produced by the expression of L lactis NZ9000. Sixty male Wistar rats were injected with DMH (40 mg/kg body weight) subcutaneously once a week for 10 wk to induce colorectal cancer. The rats were gavaged with 1 mL of endostatin at a dose of 1 x 10(8)/d and fed with the basal diet. The animals were killed after 22 wk for histopathological examination. The total time of experimental observation was 58 wk. RESULTS Rat endostatin protein was expressed in L lactis. Recombinant endostatin exhibited a significant effect on colorectal cancer (P<0.05). Furthermore, the mean survival time of the rats treated with endostatin was longer than that of the animals treated with DMH. There was no statistically significant difference between the rats treated with endostatin and those treated with DMH. The results showed that endostatin could not result in complete cure.
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Affiliation(s)
- Wei Li
- Department of Biology, Zhaoqing College, Zhaoqing 526000, Guangdong Province, China
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McDougall SR, Anderson ARA, Chaplain MAJ. Mathematical modelling of dynamic adaptive tumour-induced angiogenesis: clinical implications and therapeutic targeting strategies. J Theor Biol 2006; 241:564-89. [PMID: 16487543 DOI: 10.1016/j.jtbi.2005.12.022] [Citation(s) in RCA: 237] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2005] [Revised: 12/20/2005] [Accepted: 12/26/2005] [Indexed: 11/18/2022]
Abstract
Angiogenesis, the growth of a network of blood vessels, is a crucial component of solid tumour growth, linking the relatively harmless avascular growth phase and the potentially fatal vascular growth phase. As a process, angiogenesis is a well-orchestrated sequence of events involving endothelial cell migration, proliferation; degradation of tissue; new capillary vessel (sprout) formation; loop formation (anastomosis) and, crucially, blood flow through the network. Once there is blood flow associated with the nascent network, the subsequent growth of the network evolves both temporally and spatially in response to the combined effects of angiogenic factors, migratory cues via the extracellular matrix and perfusion-related haemodynamic forces in a manner that may be described as both adaptive and dynamic. In this paper we present a mathematical model which simultaneously couples vessel growth with blood flow through the vessels--dynamic adaptive tumour-induced angiogenesis (DATIA). This new mathematical model presents a theoretical and computational investigation of the process and highlights a number of important new targets for therapeutic intervention. In contrast to earlier flow models, where the effects of perfusion (blood flow) were essentially evaluated a posteriori, i.e. after generating a hollow network, blood flow in the model described in this paper has a direct impact during capillary growth, with radial adaptations and network remodelling occurring as immediate consequences of primary anastomoses. Capillary network architectures resulting from the dynamically adaptive model are found to differ radically from those obtained using earlier models. The DATIA model is used to examine the effects of changing various physical and biological model parameters on the developing vascular architecture and the delivery of chemotherapeutic drugs to the tumour. Subsequent simulations of chemotherapeutic treatments under different parameter regimes lead to the identification of a number of new therapeutic targets for tumour management.
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Affiliation(s)
- Steven R McDougall
- Institute of Petroleum Engineering, Heriot-Watt University, Edinburgh EH14 4AS, Scotland, UK.
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Paddenberg R, Faulhammer P, Goldenberg A, Kummer W. Hypoxia-induced increase of endostatin in murine aorta and lung. Histochem Cell Biol 2006; 125:497-508. [PMID: 16465514 DOI: 10.1007/s00418-006-0158-5] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/18/2006] [Indexed: 11/27/2022]
Abstract
In the lung, hypoxia induces pulmonary hypertension caused by vasoconstriction and vascular remodeling. Additionally, hypoxia is an inducer of angiogenesis, which is assumed to counteract pulmonary hypertension. We asked whether the anti-angiogenic factor endostatin--a cleavage product of collagen XVIII--participates in the vascular alterations induced by hypoxia. By employing Western blotting of tissue extracts of murine brain, liver and heart an endostatin fragment of 22 kDa was detectable, whereas in lung and aorta additional bands of 24 and 26 kDa were found. The amount of these larger fragments was increased in tissues obtained from mice housed for 4 days or 3 weeks at hypobaric hypoxia. By immunohistochemistry endostatin was detected in association with elastic fibers and in close neighborhood to smooth muscle cells of intrapulmonary vessels and the aorta. In the lung, the activity of matrix metalloproteinases (MMP) known to generate endostatin by cleavage of collagen XVIII was increased (MMP-2) and decreased (proMMP-9), respectively, by hypoxia. Elevated amounts of endostatin within the aortic wall of mice exposed to hypobaric hypoxia may stabilize the vascular wall by inhibition of microvascular sprouting. The surprising finding of increased endostatin in the lung presumably contributes to the development of pulmonary hypertension by reduction of angiogenesis.
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Affiliation(s)
- Renate Paddenberg
- Institute of Anatomy and Cell Biology, Justus-Liebig-University, 35385, Giessen, Germany.
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41
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Mühlhausen C, Ott N, Chalajour F, Tilki D, Freudenberg F, Shahhossini M, Thiem J, Ullrich K, Braulke T, Ergün S. Endothelial effects of 3-hydroxyglutaric acid: implications for glutaric aciduria type I. Pediatr Res 2006; 59:196-202. [PMID: 16439578 DOI: 10.1203/01.pdr.0000197313.44265.cb] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
Infants with glutaric aciduria type 1 (GA1) are subject to intracranial vascular dysfunction. Here, we demonstrate that the disease-specific metabolite 3-hydroxyglutaric acid (3-OH-GA) inhibits basal and vascular endothelial growth factor (VEGF)-induced endothelial cell migration. 3-OH-GA affects the morphology of VEGF-induced endothelial tubes in vitro because of partial disintegration of endothelial cells. These effects correlate with Ve-cadherin loss. Remarkably, 3-OH-GA treatment of human dermal microvascular endothelial cells leads to disruption of actin cytoskeleton. Local application of 3-OH-GA alone or in combination with VEGF in chick chorioallantoic membrane induces abnormal vascular dilatation and hemorrhage in vivo. The study demonstrates that 3-OH-GA reduces endothelial chemotaxis and disturbs structural vascular integrity in vitro and in vivo. These data may provide insight in the mechanisms of 3-OH-GA-induced vasculopathic processes and suggest N-methyl-D-aspartate receptor-dependent and -independent pathways in the pathogenesis of GA1.
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Mavria G, Vercoulen Y, Yeo M, Paterson H, Karasarides M, Marais R, Bird D, Marshall CJ. ERK-MAPK signaling opposes Rho-kinase to promote endothelial cell survival and sprouting during angiogenesis. Cancer Cell 2006; 9:33-44. [PMID: 16413470 DOI: 10.1016/j.ccr.2005.12.021] [Citation(s) in RCA: 254] [Impact Index Per Article: 13.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2004] [Revised: 09/21/2005] [Accepted: 12/19/2005] [Indexed: 12/30/2022]
Abstract
Inhibition of ERK-MAPK signaling by expression of dominant-negative MEK1 in the tumor vasculature suppresses angiogenesis and tumor growth. In an organotypic tissue culture angiogenesis assay, ERK-MAPK inhibition during the migratory phase results in loss of bipolarity, detachment, and cell death of isolated endothelial cells and retraction of sprouting tubules. These effects are the consequence of upregulated Rho-kinase signaling. Transient inhibition of Rho-kinase rescues the effects of ERK-MAPK inhibition in vitro and in vivo, promotes sprouting, and increases vessel length in tumors. We propose a regulatory role of Rho-kinase by ERK-MAPK during angiogenesis that acts through the control of actomyosin contractility. Our data delineate a mechanism by which ERK-MAPK promotes endothelial cell survival and sprouting by downregulating Rho-kinase signaling.
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Affiliation(s)
- Georgia Mavria
- Institute of Cancer Research, Cancer Research UK Centre for Cell and Molecular Biology, 237 Fulham Road, London SW3 6JB, United Kingdom.
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Mavria G, Harrington KJ, Marshall CJ, Porter CD. In vivo efficacy of HSV-TK transcriptionally targeted to the tumour vasculature is augmented by combination with cytotoxic chemotherapy. J Gene Med 2005; 7:263-75. [PMID: 15543524 DOI: 10.1002/jgm.662] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Retroviral vectors are suitable for targeting endothelial cells in the tumour neovasculature because of their intrinsic selectivity for proliferating cells. Previously, we inserted regulatory elements of the endothelial-specific prepro-endothelin-1 (ppET1) promoter in retroviral vectors to generate high-titre, replication-defective recombinant retroviruses that restricted gene expression to the vascular compartment of tumours. METHODS A retroviral vector was generated in which expression of herpes simplex virus thymidine kinase (HSV-TK) was transcriptionally restricted to endothelial cells, under the control of a hybrid ppET-1 LTR. Xenograft tumour models were used to determine the efficacy of targeting HSV-TK to the tumour vasculature. Subsequently, vascular-targeted gene therapy was combined with chemotherapeutic agents. RESULTS Breast or colorectal xenograft tumour growth was reduced and survival was increased in response to ganciclovir treatment. Treatment resulted in widespread vascular disruption and tumour cell apoptosis. In colorectal tumours, combination with irinotecan, a cytotoxic drug used to treat colorectal cancer, significantly increased survival compared to drug alone. No beneficial effect on survival was observed when combined with cisplatin, a cytotoxic drug not in clinical use for this tumour type. On the basis of their relative efficacies in vitro against tumour and endothelial cells, co-operativity with irinotecan likely derives from additionally targeting the peripheral tumour cells that survive the anti-vascular treatment. CONCLUSIONS We show that the ppET1-targeted vector is efficacious for therapeutic gene expression in vivo, validating a strategy targeted to tumour vasculature, and demonstrate that vascular targeting combined with appropriate chemotherapy is more effective than either therapy alone.
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Affiliation(s)
- Georgia Mavria
- Section of Cell and Molecular Biology, Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK.
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Addison CL, Nör JE, Zhao H, Linn SA, Polverini PJ, Delaney CE. The response of VEGF-stimulated endothelial cells to angiostatic molecules is substrate-dependent. BMC Cell Biol 2005; 6:38. [PMID: 16262896 PMCID: PMC1291360 DOI: 10.1186/1471-2121-6-38] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2004] [Accepted: 10/31/2005] [Indexed: 11/12/2022] Open
Abstract
Background The microenvironment surrounding cells can exert multiple effects on their biological responses. In particular the extracellular matrix surrounding cells can profoundly influence their behavior. It has been shown that the extracellular matrix composition in tumors is vastly different than that found in normal tissue with increased amounts of certain matrices such as collagen I. It has been previously demonstrated that VEGF stimulation of endothelial cells growing on type I collagen results in the induction of bcl-2 expression and enhanced endothelial cell survival. We sought to investigate whether this increased endothelial cell survival resulted in the failure of angiostatic molecules to inhibit angiogenesis. Results We now demonstrate that VEGF-induced survival on collagen I impairs the ability of three known angiostatic molecules, TSP-1, IP-10 and endostatin to inhibit endothelial cell proliferation. Apoptosis of endothelial cells, growing on collagen I, induced by TSP-1 and IP-10 was also inhibited following VEGF stimulation. In contrast, endostatin induced apoptosis in these same cells. Further analysis determined that endostatin did not decrease the expression of bcl-2 nor did it increase activation of caspase-3 in the presence of VEGF. Alternatively, it appeared that in the presence of VEGF, endostatin induced the activation of caspase-8 in endothelial cells grown on collagen I. Furthermore, only endostatin had the ability to inhibit VEGF-induced sprout formation in collagen I gels. Conclusion These data suggest that TSP-1, IP-10 and endostatin inhibit endothelial cells via different mechanisms and that only endostatin is effective in inhibiting angiogenic activities in the presence of collagen I. Our results suggest that the efficacy of angiostatic treatments may be impaired depending on the context of the extracellular matrix within the tumor environment and thus could impede the efficacy of angiostatic therapies.
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Affiliation(s)
- Christina L Addison
- Centre for Cancer Therapeutics, Ottawa Health Research Institute, 501 Smyth Rd., Ottawa Ontario, K1H 8L6, Canada
| | - Jacques E Nör
- Department of Cariology, Restorative Sciences and Endodontics, School of Dentistry, University of Michigan, 1011 North University Ave., Ann Arbor Michigan 48109-1078, USA
| | - Huijun Zhao
- Centre for Cancer Therapeutics, Ottawa Health Research Institute, 501 Smyth Rd., Ottawa Ontario, K1H 8L6, Canada
| | - Stephanie A Linn
- Oral Medicine, Pathology and Oncology, School of Dentistry, University of Michigan, 1011 North University Ave., Ann Arbor Michigan 48109-1078, USA
| | - Peter J Polverini
- Oral Medicine, Pathology and Oncology, School of Dentistry, University of Michigan, 1011 North University Ave., Ann Arbor Michigan 48109-1078, USA
| | - Christie E Delaney
- Centre for Cancer Therapeutics, Ottawa Health Research Institute, 501 Smyth Rd., Ottawa Ontario, K1H 8L6, Canada
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Schuch G, Oliveira-Ferrer L, Loges S, Laack E, Bokemeyer C, Hossfeld DK, Fiedler W, Ergun S. Antiangiogenic treatment with endostatin inhibits progression of AML in vivo. Leukemia 2005; 19:1312-7. [PMID: 15931265 DOI: 10.1038/sj.leu.2403824] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
Abstract
Increased vessel density in the bone marrow of patients with acute myeloid leukemia as well as elevated expression of proangiogenic factors by leukemic cells implies a central role of angiogenesis in hematological malignancies. Endostatin (ES), a fragment of collagen XVIII, is an endogenous inhibitor of angiogenesis that has shown therapeutic activity in solid tumors in various preclinical models. Using microencapsulation technology, we studied the therapeutic effect of ES in AML. While ES had no effect on proliferation of M1 murine leukemic cells in vitro, ES producing microbeads significantly inhibited growth of subcutaneous chloromas in SCID mice as compared to controls. In a leukemia model using M1 cells the concomitant treatment of mice with ES microbeads prolonged median survival significantly. Histological analysis revealed a decreased microvessel density and a reduced number of CD31-positive single cells, putatively endothelial progenitor cells, in the bone marrow of treated animals. Taken together, ES has inhibitory effects on neo-angiogenesis in the bone marrow and on progression of leukemia in vivo. These experiments suggest a possible therapeutic role of antiangiogenic gene therapy with ES in AML.
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Affiliation(s)
- G Schuch
- Department of Medicine, Oncology and Hematology, University Hospital Hamburg-Eppendorf, Hamburg, Germany.
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Wang YS, Eichler W, Friedrichs U, Yafai Y, Hoffmann S, Yasukawa T, Hui YN, Wiedemann P. Impact of endostatin on bFGF-induced proliferation, migration, and matrix metalloproteinase-2 expression/secretion of bovine choroidal endothelial cells. Curr Eye Res 2005; 30:479-89. [PMID: 16020281 DOI: 10.1080/02713680590959358] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
Abstract
PURPOSE To investigate the potential role of endostatin, an endogenous angiogenesis inhibitor, in the prevention of choroidal angiogenesis-related disorders. METHODS Bovine choroidal endothelial cells (CEC) were cultured and treated with basic fibroblast growth factor (bFGF) alone or combined with endostatin at concentrations ranging from 0.1 to 10 microg/ml. The proliferation and migration of CECs were evaluated by using 3, (4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) colorimetric assay and modified Boyden chamber assay, respectively. For evaluating expression and secretion of matrix metalloproteinase-2 (MMP-2), CEC-conditioned media were subjected to zymography and/or Western blot analysis, and the cells were used for semiquantitative reverse transcription polymerase chain reaction (RT-PCR) analysis. RESULTS Endostatin did not inhibit bFGF-induced or nonstimulated CEC proliferation (p > 0.05). The bFGF-induced migration was significantly inhibited by endostatin at concentrations of 1 and 10 microg/ml (p < 0.05). The bFGF-upregulated expression of mRNA in CECs and the secretion of MMP-2 protein of CECs were both suppressed by endostatin. CONCLUSIONS Inhibitory effect of endostatin on expression and secretion of MMP-2 and cell migration, but not on proliferation of CECs, could respond to its therapeutic action for choroidal neovascularization-dependent disorders.
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Affiliation(s)
- Yu-Sheng Wang
- Department of Ophthalmology, Faculty of Medicine, University of Leipzig, Liebigstrasse 10-14, 04103 Leipzig, Germany
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Abstract
CONTEXT Angiogenesis has been recognized as an important process contributing to the pathophysiology of many benign and malignant diseases. It is not surprising, therefore, that this complex process is proving to be an important regulator of both benign and malignant disease processes in the thyroid gland. This paper will review the general principles of angiogenesis and lymphangiogenesis, as well as the importance of the balance between angiogenic stimulators and inhibitors in the normal thyroid gland. We will also review how this balance is disturbed in benign and malignant thyroid conditions. Finally, we will address the role manipulation of this process may play in the development of novel treatment strategies for diseases of the thyroid. OBJECTIVE To review the literature concerning the role of angiogenesis in the thyroid gland. CONCLUSIONS Angiogenesis is an important process which has been shown to be involved in the pathophysiology of benign and malignant diseases of the thyroid gland. Manipulation of this process holds great promise for the development of novel treatments for these disorders. As the mechanisms regulating angiogenesis in the thyroid become increasingly clear, researchers will come ever closer to turning this promise into clinical reality.
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Affiliation(s)
- Jamie C Mitchell
- Department of Surgery, Section of Endocrine Surgery, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA
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Feng Y, Wu YP, Zhu XD, Zhang YH, Ma QJ. Endostatin promotes the anabolic program of rabbit chondrocyte. Cell Res 2005; 15:201-6. [PMID: 15780183 DOI: 10.1038/sj.cr.7290287] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022] Open
Abstract
Endostatin is a natural occurred angiogenesis inhibitor derived from collagenXVIII. So far its function during the angiogenesis process of bone formation and arthropathy has not been well studied yet. The present study addresses the function of endostatin in rabbit articular chondrocytes (RAC). We found that endostatin can promote RAC adhesion and spreading as well as its proliferation. In monolayer cultured RAC, CollagenII, TIMP1 and collagenXVIII transcription were up regulated by endostatin while collagenI and MMP9 were down regulated. Moreover collagenXVIII and endostatin antigens are present at synovial fluid. These findings indicate new function of endostatin as a homeostatic factor in cartilage metabolism.
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Affiliation(s)
- Yi Feng
- Department of Molecule Genetics, Beijing Institute of Biotechnology, 27 Taiping Road, Beijing 100850, China
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Kilic N, Oliveira-Ferrer L, Wurmbach JH, Loges S, Chalajour F, Neshat-Vahid S, Vahid SN, Weil J, Fernando M, Ergun S. Pro-angiogenic signaling by the endothelial presence of CEACAM1. J Biol Chem 2004; 280:2361-9. [PMID: 15536067 DOI: 10.1074/jbc.m409407200] [Citation(s) in RCA: 50] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
Here, we demonstrate the expression of carcinoembryonic antigen-related cell adhesion molecule-1 (CEACAM1) in angiogenic sprouts but not in large mother blood vessels within tumor tissue. Correspondingly, only human microvascular endothelial cells involved in in vitro tube formation exhibit CEACAM1. CEACAM1-overexpressing versus CEACAM1-silenced human microvascular endothelial cells were used in migration and tube formation assays. CEACAM1-overexpressing microvascular endothelial cells showed prolonged survival and increased tube formation when they were stimulated with vascular endothelial growth factor (VEGF), whereas CEACAM1 silencing via small interfering RNA blocks these effects. Gene array and LightCycler analyses show an up-regulation of angiogenic factors such as VEGF, VEGF receptor 2, angiopoietin-1, angiopoietin-2, tie-2, angiogenin, and interleukin-8 but a down-regulation of collagen XVIII/endostatin and Tie-1 in CEACAM1-overexpressing microvascular endothelial cells. Western blot analyses confirm these results for VEGF and endostatin at the protein level. These results suggest that constitutive expression of CEACAM1 in microvascular endothelial cells switches them to an angiogenic phenotype, whereas CEACAM1 silencing apparently abrogates the VEGF-induced morphogenetic effects during capillary formation. Thus, strategies targeting the endothelial up-regulation of CEACAM1 might be promising for antiangiogenic tumor therapy.
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Affiliation(s)
- Nerbil Kilic
- Institute of Anatomy, Medical Clinic I, University Hospital Eppendorf, D-20246 Hamburg, Germany
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50
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Chalajour F, Treede H, Ebrahimnejad A, Lauke H, Reichenspurner H, Ergun S. Angiogenic activation of valvular endothelial cells in aortic valve stenosis. Exp Cell Res 2004; 298:455-64. [PMID: 15265693 DOI: 10.1016/j.yexcr.2004.04.034] [Citation(s) in RCA: 58] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2004] [Revised: 04/16/2004] [Indexed: 11/30/2022]
Abstract
Here, we demonstrate the angiogenic response of valvular endothelial cells to aortic valve (AV) stenosis using a new ex vivo model of aortic leaflets. Histological analysis revealed neovascularization within the cusps of stenotic but not of non-stenotic aortic valves. Correspondingly, the number of capillary-like outgrowth in 3D collagen gel was significantly higher in stenotic than in non-stenotic valves. Capillary-like sprouting was developed significantly faster in stenotic than in non-stenotic valves. New capillary sprouts from stenotic aortic valves exhibited the endothelial cell markers CD31, CD34 and von-Willebrand factor (vWF) as well as carcinoembryonic antigen cell adhesion molecule-1 (CEACAM1), Tie-2 and angiogenesis inhibitor endostatin. Western blot analyses revealed a significant increase of CEACAM1 and endostatin in stenotic aortic valve tissue. Electron microscopic examinations demonstrate that these capillary-like tubes are formed by endothelial cells containing Weibel-Palade bodies. Remarkably, inter-endothelial junctions are established and basement membrane material is partially deposited on the basal side of the endothelial tubes. Our data demonstrate the capillary-like sprout formation from aortic valves and suggest a role of angiogenesis in the pathogenesis of aortic valve stenosis. These data provide new insights into the mechanisms of valvular disorders and open new perspectives for prevention and early treatment of calcified aortic stenosis.
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MESH Headings
- Aged
- Antigens, CD/metabolism
- Antigens, CD34/metabolism
- Antigens, Differentiation/metabolism
- Aortic Valve/growth & development
- Aortic Valve/pathology
- Aortic Valve/physiopathology
- Aortic Valve Stenosis/metabolism
- Aortic Valve Stenosis/pathology
- Aortic Valve Stenosis/physiopathology
- Basement Membrane/metabolism
- Basement Membrane/ultrastructure
- Capillaries/metabolism
- Capillaries/pathology
- Capillaries/physiopathology
- Cell Adhesion Molecules
- Endostatins/metabolism
- Endothelium, Vascular/metabolism
- Endothelium, Vascular/ultrastructure
- Female
- Humans
- Intercellular Junctions/metabolism
- Intercellular Junctions/ultrastructure
- Male
- Microscopy, Electron
- Models, Biological
- Neovascularization, Pathologic/metabolism
- Neovascularization, Pathologic/pathology
- Neovascularization, Pathologic/physiopathology
- Organ Culture Techniques
- Platelet Endothelial Cell Adhesion Molecule-1/metabolism
- Receptor, TIE-2/metabolism
- Weibel-Palade Bodies/metabolism
- Weibel-Palade Bodies/ultrastructure
- von Willebrand Factor/metabolism
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Affiliation(s)
- Fariba Chalajour
- Department of Cardiovascular Surgery, University Hospital Eppendorf, Hamburg, Germany
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