|ZFIN ID: ZDB-PUB-110317-35|
The integrin co-activator Kindlin-2 plays a critical role in angiogenesis in mice and zebrafish
Pluskota, E., Dowling, J.J., Gordon, N., Golden, J.A., Szpak, D., West, X.Z., Nestor, C., Ma, Y.Q., Bialkowska, K., Byzova, T., and Plow, E.F.
|Source:||Blood 117(18): 4978-4987 (Journal)|
|Registered Authors:||Dowling, Jim|
|PubMed:||21378273 Full text @ Blood|
Pluskota, E., Dowling, J.J., Gordon, N., Golden, J.A., Szpak, D., West, X.Z., Nestor, C., Ma, Y.Q., Bialkowska, K., Byzova, T., and Plow, E.F. (2011) The integrin co-activator Kindlin-2 plays a critical role in angiogenesis in mice and zebrafish. Blood. 117(18):4978-4987.
ABSTRACTKindlin-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 as compared to 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 bone marrow 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 αVβ3-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 pathological and developmental angiogenesis, which arises from defective activation of integrin αVβ3.