Fibrin and collagen differentially regulate human dermal microvascular endothelial cell integrins: Stabilization of αv/β3 mRNA by fibrin

Integrin αvβ3 is specifically but transiently expressed on the tips of capillary sprouts as they invade the fibrin clot during angiogenesis of cutaneous wound repair. Specific blocking of αvβ3 function inhibits granulation tissue formation in cutaneous wounds. The mechanisms of regulation of αvβ3 expression on human dermal microvascular endothelial cells, however, have not been fully delineated. As αvβ3 was highly expressed on capillary sprouts in 5 d wounds rich in fibrin, but was almost undetectable on blood vessels in 7 d wounds rich in collagen, we hypothesized that the extracellular matrix environment could regulate human dermal microvascular endothelial cell αvβ3 expression. To address this, human dermal microvascular endothelial cells were cultured on surfaces coated with collagen, fibronectin, and gelatin, and mRNA levels of integrin αvβ3 were determined. Compared with human dermal microvascular endothelial cells on collagen, mRNA levels of αvβ3 were higher in human dermal microvascular endothelial cells on fibronectin and on gelatin. To simulate the in vivo environment better, human dermal microvascular endothelial cells cultured on collagen were overlaid by fibrin or collagen gels prior to assessment of αv/β3 mRNA levels. αv/β3 mRNA levels were higher in human dermal microvascular endothelial cells surrounded by a three-dimensional fibrin gel compared with a collagen gel, whether angiogenic factors were present or absent. As modulation of mRNA stability is a potential regulatory mechanism for integrin expression, integrin subunit mRNA stability was assessed. β3 mRNA decayed much faster than αv, α2, and β1 mRNA. Three-dimensional fibrin gels enhanced αv/β3 mRNA stability compared with collagen gels. We propose that the provisional matrix molecules in the wound clot regulate angiogenesis associated with cutaneous wound repair through their modulation of integrin receptor expression.