A deficit in collagenase activity contributes to impaired migration of aged microvascular endothelial cells

Angiogenesis is impaired in aging. Delayed neovascularization is due, in pa rt, to slowed endothelial cell migration. Migration requires an optimal lev el of adhesion to matrix proteins, a process mediated by matrix-degrading m etalloproteases (MMPs) such as MMP1. To determine whether impaired angiogen esis in aging is associated with altered synthesis and activity of MMP1. we examined the expression of collagenase and tissue inhibitor of metalloprot ease 1 (TIMP1) by immunostain of angiogenic sponge implants from young and aged mice. To characterize the relevance of MMP activity during the movemen t of aged endothelial cells, the secretion of MMP1 and TIMP1 by late-passag e human microvascular endothelial cells (hmEC aged in vitro) and their non- aged (young) counterparts was quantified. The migration of aged human micro vascular endothelial cells and the effect of inhibition of TIMP1 on the mig ration of aged hmEC or collagen I was also measured. Relative to young mice , granulation tissue from aged mice showed less expression of collagenase a nd increased expression of TIMP1. In vitro, aged hmEC were deficient in MMP 1 secretion (55 +/- 13% relative to young cells) and activity but showed in creased expression of TIMP1 (280 +/- 109% relative to young cells). Aged hm EC migrated significantly less distance than did young hmEC over a 5-day pe riod (59 +/- 8% relative to young cells). In the presence of a blocking ant ibody to TIMP1, aged hmEC showed a significant increase in the distance mig rated on collagen I over a 5 day period (142 +/- 11% relative to untreated aged hmEC). We propose that deficient MMP1 activity contributes to impaired cellular movement in aged microvascular endothelial cells and that perturb ations that enhance collagenase activity increase their migratory ability a nd angiogenic potential. J. Cell. Biochem. 77:116-126, 2000. (C) 2000 Wiley -Liss, Inc.