Endothelial 5 and v integrins cooperate in remodeling of the vasculature during development

Howard Hughes Medical Institute, Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Development (Impact Factor: 6.46). 07/2010; 137(14):2439-49. DOI: 10.1242/dev.049551
Source: PubMed


Integrin cell adhesion receptors and fibronectin, one of their extracellular matrix ligands, have been demonstrated to be important for angiogenesis using functional perturbation studies and complete knockout mouse models. Here, we report on the roles of the alpha5 and alphav integrins, which are the major endothelial fibronectin receptors, in developmental angiogenesis. We generated an integrin alpha5-floxed mouse line and ablated alpha5 integrin in endothelial cells. Unexpectedly, endothelial-specific knockout of integrin alpha5 has no obvious effect on developmental angiogenesis. We provide evidence for genetic interaction between mutations in integrin alpha5 and alphav and for overlapping functions and compensation between these integrins and perhaps others. Nonetheless, in embryos lacking both alpha5 and alphav integrins in their endothelial cells, initial vasculogenesis and angiogenesis proceed normally, at least up to E11.5, including the formation of apparently normal embryonic vasculature and development of the branchial arches. However, in the absence of endothelial alpha5 and alphav integrins, but not of either alone, there are extensive defects in remodeling of the great vessels and heart resulting in death at ~E14.5. We also found that fibronectin assembly is somewhat affected in integrin alpha5 knockout endothelial cells and markedly reduced in integrin alpha5/alphav double-knockout endothelial cell lines. Therefore, neither alpha5 nor alphav integrins are required in endothelial cells for initial vasculogenesis and angiogenesis, although they are required for remodeling of the heart and great vessels. These integrins on other cells, and/or other integrins on endothelial cells, might contribute to fibronectin assembly and vascular development.

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    • "In vivo, FN1-binding integrin heterodimers containing α4 or α3 chains do not appear to cooperate with integrin α5β1 during early embryogenesis (Yang et al., 1999). αv-containing integrins cooperate with integrin α5β1 in early mouse embryogenesis to facilitate gastrulation as well as in midgestation, during remodeling of the pharyngeal arch arteries (Yang et al., 1999; van der Flier et al., 2010). In zebrafish, αv-containing integrins were shown to be important for the establishment of the left–right asymmetry by regulating morphogenesis of the Kupffer's vesicle. "
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    ABSTRACT: The node and notochord (and their equivalents in other species) are essential signaling centers, positioned along the plane of bilateral symmetry in developing vertebrate embryos. However, genes and mechanisms regulating morphogenesis of these structures and their placement along the embryonic midline are not well understood. In this work, we provide the first evidence that the position of the node and the notochord along the bilateral plane of symmetry are under genetic control and are regulated by integrin α5β1 and fibronectin in mice. We found that the shape of the node is often inverted in integrin α5-null and fibronectin-null mutants, and that the positioning of node and the notochord is often skewed away from the perceived plane of embryonic bilateral of symmetry. Our studies also show that the shape and position of the notochord are dependent on the shape and embryonic placement of the node. Our studies suggest that fibronectin regulates the shape of the node by affecting apico-basal polarity of the nodal cells. Taken together, our data indicate that cell-extracellular matrix interactions mediated by integrin α5β1 and fibronectin regulate the geometry of the node as well as the placement of the node and notochord along the plane of bilateral symmetry in the mammalian embryo.
    Full-text · Article · Jun 2014 · Biology Open
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    • "During the formation and remodeling of blood vessels, EC adhesion to provisional extracellular matrix (ECM) proteins, such as fibronectin (FN) and vitronectin (VN), is mediated by α5 and αv integrin receptors6,7 that cooperate in remodeling the vasculature during angiogenesis8. Small GTPases belonging to the R-Ras branch of the wider Ras superfamily9, namely R-Ras (also known as R-Ras1), TC21 (also known as R-Ras2), and M-Ras (also known as R-Ras3), have all been reported to enhance integrin-mediated cell-to-ECM adhesion10. "
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    ABSTRACT: During developmental and tumor angiogenesis, semaphorins regulate blood vessel navigation by signaling through plexin receptors that inhibit the R-Ras subfamily of small GTPases. R-Ras is mainly expressed in vascular cells, where it induces adhesion to the extracellular matrix (ECM) through unknown mechanisms. We identify the Ras and Rab5 interacting protein RIN2 as a key effector that in endothelial cells interacts with and mediates the pro-adhesive and -angiogenic activity of R-Ras. Both R-Ras-GTP and RIN2 localize at nascent ECM adhesion sites associated with lamellipodia. Upon binding, GTP-loaded R-Ras converts RIN2 from a Rab5 guanine nucleotide exchange factor (GEF) to an adaptor that first interacts at high affinity with Rab5-GTP to promote the selective endocytosis of ligand-bound/active β1 integrins and then causes the translocation of R-Ras to early endosomes. Here, the R-Ras/RIN2/Rab5 signaling module activates Rac1-dependent cell adhesion via TIAM1, a Rac GEF that localizes on early endosomes and is stimulated by the interaction with both Ras proteins and the vesicular lipid phosphatidylinositol 3-monophosphate. In conclusion, the ability of R-Ras-GTP to convert RIN2 from a GEF to an adaptor that preferentially binds Rab5-GTP allows the triggering of the endocytosis of ECM-bound/active β1 integrins and the ensuing funneling of R-Ras-GTP toward early endosomes to elicit the pro-adhesive and TIAM1-mediated activation of Rac1.
    Full-text · Article · Jul 2012 · Cell Research
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    • "Fibrillin stimulates LEC adhesion through the RGD-binding integrins α5β1 and αvβ3 [105]. However, the importance of α5β1 and αvβ3 to lymphatic endothelium is questionable, since mice deficient for both α5 and αv integrin subunits in endothelial cells show no apparent developmental defects in lymphangiogenesis or lymphatic function [21]. Mutations in fibrillin genes are associated with Marfan's syndrome, and fibrillin knockout mice recapitulate this phenotype [106]. "
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    ABSTRACT: In the 1970s, the late Judah Folkman postulated that tumors grow proportionately to their blood supply and that tumor angiogenesis removed this limitation promoting growth and metastasis. Work over the past 40 years, varying from molecular examination to clinical trials, verified this hypothesis and identified a host of therapeutic targets to limit tumor angiogenesis, including the integrin family of extracellular matrix receptors. However, the propensity for some tumors to spread through lymphatics suggests that lymphangiogenesis plays a similarly important role. Lymphangiogenesis inhibitors reduce lymph node metastasis, the leading indicator of poor prognosis, whereas inducing lymphangiogenesis promotes lymph node metastasis even in cancers not prone to lymphatic dissemination. Recent works highlight a role for integrins in lymphangiogenesis and suggest that integrin inhibitors may serve as therapeutic targets to limit lymphangiogenesis and lymph node metastasis. This review discusses the current literature on integrin-matrix interactions in lymphatic vessel development and lymphangiogenesis and highlights our current knowledge on how specific integrins regulate tumor lymphangiogenesis.
    Full-text · Article · Feb 2012 · International Journal of Cell Biology
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