RhoA mediates flow-induced endothelial sprouting in a 3-D tissue analogue of angiogenesis

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Endothelial cells (ECs) integrate signals from the local microenvironment to guide their behaviour. RhoA is involved in vascular endothelial growth factor (VEGF)-driven angiogenesis, but its role in mechanotransduction during sprouting has not been established. Using dominant negative cell transfections in a microfluidic device that recapitulates angiogenic sprouting, we show that endothelial cells respond to interstitial flow in a RhoA-dependent manner while invading a 3-D extracellular matrix. Furthermore, RhoA regulates flow-induced, but not VEGF gradient-induced, tip cell filopodial extensions. Thus, RhoA pathways mediate mechanically-activated but not VEGF-induced endothelial morphogenesis.