Inhibition of TIMP1 enhances angiogenesis in vivo and cell migration in vitro.

Neovascular invasion into a 3-dimensional matrix is controlled, in part, by matrix metalloproteinases (MMPs) and their inhibitors, tissue inhibitors of metalloproteinases (TIMPs). We tested the hypothesis that increasing MMP activity, via a specific blocking antibody to TIMP1, would enhance fibrovascular invasion into a PVA sponge. In vivo, inhibition of TIMP1 doubled the amount of angiogenic invasion (percentage area of invasion 33.5 +/- 3.5 vs 16.9 +/- 9.5, P = 0.003). The blocking antibody to TIMP1 did not increase the proportion of cells that were proliferating in the sponge implants, underscoring the importance of migration. In vitro, human microvascular endothelial cells (hmEC) and dermal fibroblasts treated with the antibody did not secrete greater amounts of collagenase but migrated significantly farther on collagen I (increase in distance migrated 26.6 +/- 9.4%, P = 0.003). Human dermal microvascular endothelial cells exposed to the TIMP1 blocking antibody exhibited a significant change in cell shape to a more elongated morphology. In conclusion, inhibition of TIMP1 increased angiogenesis into a PVA sponge in vivo and enhanced the migration of dermal hmEC and fibroblasts on collagen I in vitro. We propose that blocking TIMP1 improves angiogenesis by increasing cell motility during fibrovascular invasion.