Role of extracellular matrix in vascular morphogenesis

Our laboratory studies how extracellular matrices such as three‐dimensional (3D) collagen matrices regulate human endothelial cell (EC) assembly into networks of tubes with defined lumens. This process is dependent on integrin recognition of the collagen matrix (alpha2 beta1) as well as the downstream integrin signaling effectors, Cdc42 and Rac1. In addition, these events require the membrane‐type metalloproteinase, MT1‐MMP. We hypothesize that coordinated signaling between these receptors and signaling effectors is required for human ECs to form lumens and tubular networks in 3D collagen matrices. Interestingly, ECs seeded in 3D matrices containing laminin using the same culture conditions results in a lack of lumen formation and tube morphogenesis. Thus, collagen matrices stimulate vascular morphogenesis while laminin‐rich matrices do not support these events suggesting that the latter matrices are either non‐permissive or are actively inhibitory to morphogenesis. Due to the fact that EC vessel maturation is accompanied by basement membrane formation which is rich in laminin matrices suggests the possibility that laminin isoforms may be assembled which actively inhibit tube morphogenesis in order to facilitate tube stabilization. We have recently reported that pericyte‐induced stabilization of EC‐lined tubes occurs in part through delivery of the heparan sulfate‐ and basement membrane matrix‐binding tissue inhibitor of metalloproteinase (TIMP)‐3. Thus, TIMP‐3 and laminins together may act as inhibitory molecules presented by basement membranes to block vascular morphogenesis and promote vascular stabilization.