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

Abstract

Angiogenesis is impaired in aging. Delayed neovascularization is due, in part, to slowed endothelial cell migration. Migration requires an optimal level of adhesion to matrix proteins, a process mediated by matrix-degrading metalloproteases (MMPs) such as MMP1. To determine whether impaired angiogenesis in aging is associated with altered synthesis and activity of MMP1, we examined the expression of collagenase and tissue inhibitor of metalloprotease 1 (TIMP1) by immunostain of angiogenic sponge implants from young and aged mice. To characterize the relevance of MMP activity during the movement of aged endothelial cells, the secretion of MMP1 and TIMP1 by late-passage human microvascular endothelial cells (hmEC aged in vitro) and their non-aged (young) counterparts was quantified. The migration of aged human microvascular endothelial cells and the effect of inhibition of TIMP1 on the migration of aged hmEC or collagen I was also measured. Relative to young mice, granulation tissue from aged mice showed less expression of collagenase and increased expression of TIMP1. In vitro, aged hmEC were deficient in MMP1 secretion (55 +/- 13% relative to young cells) and activity but showed increased expression of TIMP1 (280 +/- 109% relative to young cells). Aged hmEC migrated significantly less distance than did young hmEC over a 5-day period (59 +/- 8% relative to young cells). In the presence of a blocking antibody to TIMP1, aged hmEC showed a significant increase in the distance migrated 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 perturbations that enhance collagenase activity increase their migratory ability and angiogenic potential.

Tumor Necrosis Factor-α Receptor p75 Is Required in Ischemia-Induced Neovascularization

“…22,26 -28 Specifically, investigators have delineated deficiencies in several components of ischemiainduced neovascularization, including inhibition of EC proliferation and function 22,29,30 and impaired expression of angiogenic growth factors, such as VEGF, bFGF, and transforming growth factor-␤. 22,31,32 Impaired signaling by TNF-␣ and other cytokines in ECs has been correlated with enhanced apoptotic responses in the cutaneous microvasculature in adult tissue.…”

Arterial and Cardiac Aging: Major Shareholders in Cardiovascular Disease Enterprises

“…36 Expression of TGF-␤1 and the matrix protein type-1 collagen are decreased in microvascular endothelial cells from aged mice and are associated with alterations in MMP-1 and tissue inhibitor of metalloproteinase-1. 37,38 Angiogenesis can be modulated with the administration of angiogenic growth factors such as vascular endothelial growth factor (VEGF). Interestingly, expression of VEGF and hypoxia inducible factor 1 (HIF-1) activity are decreased with aging.…”

Extracellular influences on tumour angiogenesis in the aged host

“…Within the context of tumour progression and angiogenesis, the matrix metalloproteinases (MMPs) are the most widely studied class of molecules. Although it is a widely held belief that tissue levels of MMPs increase with ageing, more recent studies indicate that changes in MMP activity in most aged organs reflect a deregulation rather than pervasive increases (Reed et al, 2000). Accordingly, some aged tissues show decreased matrix turnover at the same time others demonstrate increased MMP activity.…”