Control of microvascular tube assembly by endothelial cell‐pericyte interactions

Abstract

Endothelial cell (EC) tube morphogenesis is controlled by downstream signals derived from a cell surface metalloproteinase, MT1‐MMP, the Rho GTPases, Cdc42 and Rac1, and the α2β1 integrin. These signals promote lumen formation and interconnection of neighboring cells to form multicellular tube networks in 3D collagen matrices. This process depends on Cdc42‐mediated signaling and involves the downstream effectors, Pak2, Pak4, the cell polarity protein, Par3, and the protein kinase C isoforms, epsilon and zeta. Also, during tube formation, ECs generate MT1‐MMP‐dependent proteolyzed spaces, termed vascular guidance tunnels, which represent physical imprints in the matrix allowing for rapid cellular movement and tube remodeling. In EC‐pericyte cocultures, marked recruitment of pericytes occurs into these vascular guidance tunnels and they are distributed in a polarized fashion along the ablumenal surface of EC tubes. These tunnels facilitate dynamic migration of ECs and pericytes, leading to deposition of basement membrane matrix components (only occurs with pericytes) and EC tube stabilization. Thus, EC microvascular tube assembly is a function of initial EC signaling and morphogenic events leading to vascular guidance tunnel formation and downstream stabilization signals catalyzed by EC‐pericyte interactions within these tunnel spaces. Supported by NIH grants HL59373 and HL79460.