Pericyte contraction generates angiostatic effect via cell force-dependent activation of TGFβ

Pericytes are phenotypically plastic and capable of switching between contractile and proliferative phenotypes, similar to vascular smooth muscle cells. The intimate interaction of contractile pericytes with endothelial cells (ECs) is essential to the maturation, quiescence, and stability of the capillary and microvascular endothelium. However, the mechanistic link between pericyte contraction and vascular stability is unknown. It is known that TGFβ has dual pro- and antiangiogenic effects depending on the downstream Smad signaling. Here, we show that R-Ras-mediated contractility in pericytes activates TGFβ by integrin-dependent, actomyosin-generated cell traction force. This TGFβ activation, in turn, promotes the quiescence of ECs via the ALK5-Smad2/3 axis of the TGFβ pathway in ECs, but not the Smad1/5 axis of the TGFβ pathway. Furthermore, pericyte-targeted deletion of Rras in mice resulted in impaired pericyte contractility and a significant reduction of Smad2/3 phosphorylation in ECs, accompanied by increased tumor angiogenesis and vessel deformation in the skeletal muscle. These observations suggest that pericytes use the cell force to maintain the quiescence of the endothelium by elevating the local bioavailability of active TGFβ. Our findings provide a mechanism by which pericytes stabilize blood vessels.