Journal
AMERICAN JOURNAL OF PATHOLOGY
Volume 175, Issue 3, Pages 1338-1347Publisher
ELSEVIER SCIENCE INC
DOI: 10.2353/ajpath.2009.090234
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Funding
- NATIONAL CANCER INSTITUTE [R01CA047282, R01CA039481, R01CA120975] Funding Source: NIH RePORTER
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [P01HL062250, R01HL053590] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM [T32AA007463] Funding Source: NIH RePORTER
- NCI NIH HHS [R01 CA47282, R01 CA120975, R01 CA039481, R01 CA047282, R01 CA39481] Funding Source: Medline
- NHLBI NIH HHS [R01 HL53590, P01 HL062250, R01 HL62250, R01 HL053590] Funding Source: Medline
- NIAAA NIH HHS [T32 AA07463, T32 AA007463] Funding Source: Medline
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The alpha 2 beta 1 integrin receptor plays a key role in angiogenesis. Here we investigated the effects of small molecule inhibitors (SMIs) designed to disrupt integrin alpha 2 I or 131 I-like domain function on angiogenesis. in unchallenged endothelial cells, fibrillar collagen induced robust capillary morphogenesis. In contrast, tube formation was significantly reduced by SM1496, a beta 1 I-like domain inhibitor and by function-blocking anti-alpha 2 beta 1 but not -alpha 1 beta 1 antibodies. Endothelial cells bound fluorescein-labeled collagen I fibrils, an interaction specifically inhibited by SM1496. Moreover, SM1496 caused cell retraction and cytoskeletal collapse of endothelial cells as well as delayed endothelial cell wound heating. SMI activities were examined in vivo by supplementing the growth medium of zebrafish embryos expressing green fluorescent protein under the control of the vascular endothelial growth factor receptor-2 promoter. SM1496, but not a control compound, interfered with angiogenesis in vivo by reversibly inhibiting sprouting from the axial vessels. We further characterized zebrafish alpha 2 integrin and discovered that this integrin is highly conserved, especially the I domain. Notably, a similar vascular phenotype was induced by morpholino-mediated knockdown of the integrin alpha 2 subunit. By live videomicroscopy, we confirmed that the vessels were largely nonfunctional in the absence of alpha 2 beta 1 integrin. Collectively, our results provide strong biochemical and genetic evidence of a central role for alpha 2 beta 1 integrin in experimental and developmental angiogenesis. (Am J Pathol 2009, 175:1138-1347; DOI: 10.2353/ajpath.2009.090234)
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