TY - JOUR
T1 - Blood Vessel Tubulogenesis Requires Rasip1 Regulation of GTPase Signaling
AU - Xu, Ke
AU - Sacharidou, Anastasia
AU - Fu, Stephen
AU - Chong, Diana C.
AU - Skaug, Brian
AU - Chen, Zhijian J.
AU - Davis, George E.
AU - Cleaver, Ondine
N1 - Funding Information:
We thank T. Carroll for gene targeting instructions, knockout vector, and antibodies. We also thank J. Rossant and E. Keshet for the Flk1-EGFP/lacZ mice; Mark Henkemeyer for the EphB4-LacZ mice; Sanford Shattil for the WOW-1 antibody; James Amatruda for assistance with zebrafish; and Jose Cabrera for help with figures. We thank the UTSW Core Facilities: Imaging, Transgenic, Peptide Synthesis, and TEM cores for assistance. We thank N. Mitin, E. Olson, J. Hsieh, P. Krieg, M. Tallquist, and M. Buszczak for critical reading of the manuscript and N. Mitin, T. Carroll, and the CCLARTB group for essential discussions. This work is supported by NIH Predoctoral training grant GM007062 (B.S.), AHA Predoctoral fellowship 09PRE2070035 (K.X.), NIH HL59373 (G.E.D.) and NIH DK079862, AHA Grant-in-Aid 0755054Y, and the Basil O'Connor March of Dimes Award (O.C.).
PY - 2011/4/19
Y1 - 2011/4/19
N2 - Cardiovascular function depends on patent blood vessel formation by endothelial cells (ECs). However, the mechanisms underlying vascular " tubulogenesis" are only beginning to be unraveled. We show that endothelial tubulogenesis requires the Ras interacting protein 1, Rasip1, and its binding partner, the RhoGAP Arhgap29. 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). Similarly, depletion of either Rasip1 or 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. This study identifies Rasip1 as a unique, endothelial-specific regulator of Rho GTPase signaling, which is essential for blood vessel morphogenesis.
AB - Cardiovascular function depends on patent blood vessel formation by endothelial cells (ECs). However, the mechanisms underlying vascular " tubulogenesis" are only beginning to be unraveled. We show that endothelial tubulogenesis requires the Ras interacting protein 1, Rasip1, and its binding partner, the RhoGAP Arhgap29. 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). Similarly, depletion of either Rasip1 or 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. This study identifies Rasip1 as a unique, endothelial-specific regulator of Rho GTPase signaling, which is essential for blood vessel morphogenesis.
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U2 - 10.1016/j.devcel.2011.02.010
DO - 10.1016/j.devcel.2011.02.010
M3 - Article
C2 - 21396893
AN - SCOPUS:79954554710
SN - 1534-5807
VL - 20
SP - 526
EP - 539
JO - Developmental cell
JF - Developmental cell
IS - 4
ER -