Integrin beta 1- and beta 3-mediated endothelial cell migration is triggered through distinct signaling mechanisms.

Leavesley, David I.; Schwartz, Martin A.; Rosenfeld, Mauricio; Cheresh, David A.

doi:10.1083/jcb.121.1.163

Cited by 366 publications

(196 citation statements)

References 46 publications

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“…Together, these observations all point to a role of kindlin-2 in regulating ␣V␤3 activation. The pivotal role of kindlin-2-dependent ␤3 integrin activation in angiogenesis is consistent with extensive evidence demonstrating the importance of ␣V␤3 in angiogenesis (reviewed in Avraamides et al 5 ) using Abs, peptides, small molecules, or antisense approaches in vitro 33,34 and in vivo. 4,35 Angiogenesis induced by growth factors or tumors is also suppressed in knock-in mice expressing Y747F/Y759F mutations in the ␤3 cytoplasmic tail of ␣V␤3.…”

Section: Discussionsupporting

confidence: 51%

The integrin coactivator Kindlin-2 plays a critical role in angiogenesis in mice and zebrafish

Pluskota

Dowling

Gordon

et al. 2011

Blood

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Kindlin-2, a widely distributed cytoskeletal protein, has been implicated in integrin activation, and its absence is embryonically lethal in mice and causes severe developmental defects in zebrafish. Knockdown of kindlin-2 levels in endothelial cells resulted in defective adhesive and migratory responses, suggesting that angiogenesis might be aberrant even with partial reduction of kindlin-2. This hypothesis has now been tested in the kindlin-2 ؉/؊ mice. RM1 prostate tumors grown in kindlin-2 ؉/؊ mice had fewer blood vessels, which were thinner and shorter and supported less tumor growth compared with wild-type littermates. The vessels that did form in the kindlin-2 ؉/؊ mice lacked smooth muscle cells and pericytes and had thinner basement membranes, indicative of immature vessels. VEGF-induced angiogenesis in matrigel implants was also abnormal in the kindlin-2 ؉/؊ mice. Vessels in the kindlin-2 ؉/؊ mice were leaky, and BM transplantation from kindlin-2 ؉/؊ to WT mice did not correct this defect. Endothelial cells derived from kindlin-2 ؉/؊ mice had integrin expression levels similar to WT mice but reduced ␣V␤3-dependent signaling, migration, adhesion, spreading, and tube formation. Developmental angiogenesis was markedly impaired by kindlin-2 morpholinos in zebrafish. Taken together, kindlin-2 plays an important role in pathologic and developmental angiogenesis, which arises from defective activation of integrin ␣V␤3. IntroductionAlthough endothelial cells (ECs) are the primary cell type that forms blood vessel tubes, other cell types, including BM-derived cells, smooth muscle cells, and pericytes, are all engaged in forming blood-bearing conduits. Growth factor-growth factor receptor interactions are involved in initial recruitment of these cells while other ligand-receptor systems govern migration of the responding cells into angiogenic tissues (reviewed in Folkman 1 ). Among the cellular receptors that specialize in regulating the adhesive and migratory responses of cells during angiogenesis are members of the integrin family. 2 Integrins of the ␤1 and ␤3 subfamilies on ECs have been implicated in angiogenesis in vivo through knockout 3 and inhibitor approaches 4 and integrin ␣V␤3 and ␣5␤1 are targets of antiangiogenic drugs for cancer treatment (reviewed in Avraamides et al 5 ).The regulation of integrin function in angiogenesis as well as many other responses depends on their ability to undergo activation, a rapid transition from a low-to a high-affinity state for recognition of their ligands. Particularly relevant to angiogenesis is the ability of VEGF to activate integrin ␣V␤3 and ␣5␤1 by engaging one of its EC receptors, VEGFR2. 6 Indeed, VEGFR2 and integrin ␣V␤3 can form a physical complex in EC and influence the functions of each other. 6,7 Two sets of cytoskeletal proteins, the talins and the kindlins, bind to the ␤ cytoplasmic tails and are now known to be involved in integrin activation. [8][9][10] Talin has long been known to be critical for integrin activation 11 and more recent studies have sh...

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Section: Discussionsupporting

confidence: 51%

The integrin coactivator Kindlin-2 plays a critical role in angiogenesis in mice and zebrafish

Pluskota

Dowling

Gordon

et al. 2011

Blood

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“…Recent work in our laboratory revealed that ETS-1 converts EC to an invasive phenotype by inducing the expression of proteases including u-PA, MMP-1, MMP-3, and MMP-9, as well as integrin β3 subunit as target genes in ECs. 11,31) u-PA, MMP-1, MMP-3, and MMP-9 are responsible for degradation of extracellular matrices, whereas u-PA 32,33) and integrin β3 34,35) are responsible for cell migration. Therefore, the inhibitory effect of PD98059 on cell migration may derive at least in part from the impaired expression of ETS-1 target genes.…”

Section: Discussionmentioning

confidence: 99%

Roles of Extracellular Signal‐regulated Kinase 1/2 and p38 Mitogen‐activated Protein Kinase in the Signal Transduction of Basic Fibroblast Growth Factor in Endothelial Cells during Angiogenesis

Tanaka

Abé

Sato

1999

Japanese Journal of Cancer Research

122

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“…Mediates endothelial cell attachment, spreading, and migration 419 Inhibits endothelial cell apoptosis 199 Highly expressed on activated endothelial cells 420,421 Present on angiogenic capillary sprouts 197,198 Localizes MMP-2 to capillary sprouts 198 Required for FGF-stimulated angiogenesis in vivo 195,196 α v β 5 Required for VEGF-stimulated angiogenesis in vivo 195,196 MMPs…”

Section: Ecm Extracellular Matrixmentioning

confidence: 99%

The Role of Mechanical Stresses in Angiogenesis

Shiu

Weiss

Hoying

et al. 2005

Crit Rev Biomed Eng

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ABSTRACT:Angiogenesis is the formation of new capillary blood vessels from preexisting vessels. It is involved in many normal and diseased conditions, as well as in the application of tissue-engineered products. Th ere has been extensive eff ort made to develop strategies for controlling pathological angiogenesis and for promoting vascularization in biomedical engineering applications. Central to advancing these strategies is a mechanistic understanding of the angiogenic process. Angiogenesis is tightly regulated by local tissue environmental factors, including soluble molecules, extracellular matrices, cell-cell interactions, and diverse mechanical forces. Great advances have been made in identifying the biochemical factors and intracellular signaling pathways that mediate the control of angiogenesis. Th is review focuses on work that explores the biophysical aspect of angiogenesis regulation. Specifi cally, we discuss the role of cell-generated forces, counterforces from the extracellular matrix, and mechanical forces associated with blood fl ow and extravascular tissue activity in the regulation of angiogenesis. Because angiogenesis occurs in a mechanically dynamic environment, future investigations should aim at understanding how cells integrate chemical and mechanical signals so that a rational approach to controlling angiogenesis will become possible. In this regard, computational models that incorporate multiple epigenetic factors to predict capillary patterning will be useful.

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Integrin beta 1- and beta 3-mediated endothelial cell migration is triggered through distinct signaling mechanisms.

Cited by 366 publications

References 46 publications

The integrin coactivator Kindlin-2 plays a critical role in angiogenesis in mice and zebrafish

The integrin coactivator Kindlin-2 plays a critical role in angiogenesis in mice and zebrafish

Roles of Extracellular Signal‐regulated Kinase 1/2 and p38 Mitogen‐activated Protein Kinase in the Signal Transduction of Basic Fibroblast Growth Factor in Endothelial Cells during Angiogenesis

The Role of Mechanical Stresses in Angiogenesis

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