Rasipa Regulates Vascular Tubulogenesis

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Title: Rasipa Regulates Vascular Tubulogenesis
Author: Xu, Ke
Abstract: Cardiovascular function depends on patent blood vessel formation by endothelial cells (ECs ) . However very little is known about the mechanisms underlying vascular ‘tubulogenesis’ . This study identifies Rasip1 as a unique , endothelial -specific regulator of Rho GTPase signaling , which is essential for endothelial lumen morphogenesis . We found that Rasip1 is strongly expressed in vascular endothelial cells throughout development across species . Similar to the well -characterized vascular markers VEGFR2 and PECAM , Rasip1 is specifically expressed in angioblasts prior to vessel formation , in the initial embryonic vascular plexus , in the growing blood vessels during angiogenesis and in the endothelium of mature blood vessels into the postnatal period . Rasip1 expression is undetectable in VEGFR2 null embryos , which lack endothelial cells , suggesting that Rasip1 is endothelial -specific . Ablation of Rasip1 both in vitro and in vivo strongly affects vascular integrity . Specifically , siRNA -mediated reduction of Rasip1 severely impairs angiogenesis in endothelial cell cultures , and morpholino knockdown experiments demonstrate that Rasip1 is required for embryonic vessel formation in frog embryos . Mice lacking Rasip1 fail to form patent lumens in all blood vessels , including the early endocardial tube . Rasipl null angioblasts fail to properly localize the polarity determinant Par3 and display defective cell polarity , resulting in mislocalized junctional complexes and loss of adhesion to extracellular matrix (ECM ) . Depletion of either Rasip1 or its binding partner RhoGAP Arhgap29 in cultured ECs blocks in vitro lumen formation , fundamentally alters the cytoskeleton and reduces integrin -dependent adhesion to ECM . These defects result from increased RhoA /ROCK /myosin II activity and blockade of Cdc42 and Rac1 signaling . Together , our work identify Rasip1 as a novel endothelial factor that plays an essential role in vascular tubulogenesis .
URI: http : / /hdl .handle .net /2152 .5 /958
Date: 2011-12-15


Rasipa Regulates Vascular Tubulogenesis. Graduate School of Biomedical Sciences. Available electronically from http : / /hdl .handle .net /2152 .5 /958 .

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