PUBLICATION
A Key Role for the Integrin {alpha}2{beta}1 in Experimental and Developmental Angiogenesis
- Authors
- San Antonio, J.D., Zoeller, J.J., Habursky, K., Turner, K., Pimtong, W., Burrows, M., Choi, S., Basra, S., Bennett, J.S., Degrado, W.F., and Iozzo, R.V.
- ID
- ZDB-PUB-090828-16
- Date
- 2009
- Source
- The American journal of pathology 175(3): 1338-1347 (Journal)
- Registered Authors
- Iozzo, Renato, Pimtong, Wittaya
- Keywords
- none
- MeSH Terms
-
- Animals
- Animals, Genetically Modified
- Antibodies, Blocking
- Cell Adhesion/physiology
- Cell Movement/physiology
- Cells, Cultured
- Collagen
- Dipeptides/pharmacology*
- Endothelium, Vascular/cytology
- Endothelium, Vascular/physiology
- Humans
- Integrin alpha2beta1/antagonists & inhibitors
- Integrin alpha2beta1/physiology*
- Neovascularization, Physiologic/physiology*
- Protein Structure, Tertiary
- Vascular Endothelial Growth Factor Receptor-2/physiology
- Zebrafish
- PubMed
- 19700757 Full text @ Am. J. Pathol.
Citation
San Antonio, J.D., Zoeller, J.J., Habursky, K., Turner, K., Pimtong, W., Burrows, M., Choi, S., Basra, S., Bennett, J.S., Degrado, W.F., and Iozzo, R.V. (2009) A Key Role for the Integrin {alpha}2{beta}1 in Experimental and Developmental Angiogenesis. The American journal of pathology. 175(3):1338-1347.
Abstract
The alpha2beta1 integrin receptor plays a key role in angiogenesis. Here we investigated the effects of small molecule inhibitors (SMIs) designed to disrupt integrin alpha2 I or beta1 I-like domain function on angiogenesis. In unchallenged endothelial cells, fibrillar collagen induced robust capillary morphogenesis. In contrast, tube formation was significantly reduced by SMI496, a beta1 I-like domain inhibitor and by function-blocking anti-alpha2beta1 but not -alpha1beta1 antibodies. Endothelial cells bound fluorescein-labeled collagen I fibrils, an interaction specifically inhibited by SMI496. Moreover, SMI496 caused cell retraction and cytoskeletal collapse of endothelial cells as well as delayed endothelial cell wound healing. 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. SMI496, but not a control compound, interfered with angiogenesis in vivo by reversibly inhibiting sprouting from the axial vessels. We further characterized zebrafish alpha2 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 alpha2 subunit. By live videomicroscopy, we confirmed that the vessels were largely nonfunctional in the absence of alpha2beta1 integrin. Collectively, our results provide strong biochemical and genetic evidence of a central role for alpha2beta1 integrin in experimental and developmental angiogenesis.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping