Enhanced angiogenesis characteristic of SPARC‐null mice disappears with age

Abstract

The impairment of angiogenesis in aging has been attributed, in part, to alterations in proteins associated with the extracellular matrix (ECM). SPARC (secreted protein acidic and rich in cysteine/osteonectin/BM-40) is a matricellular protein that regulates endothelial cell function as well as cell-ECM interactions. We have previously shown that angiogenesis, as reflected by fibrovascular invasion into subcutaneously implanted polyvinyl alcohol (PVA) sponges, is increased in SPARC-null mice (6-9 months of age) relative to their wild-type (WT) counterparts. In this study, we define the influence of aging on (a) the expression of SPARC and (b) fibrovascular invasion into sponge implants in SPARC-null and WT mice. The expression of SPARC in fibroblasts and endothelial cells derived from young donors (humans mean age less than 30 years and mice 4-6 months of age) and old donors (humans mean age over 65 years and mice 22-27 months of age) decreased 1.6 to 2.3-fold with age. Analysis of fibrovascular invasion into sponges implanted into old (22-27 months) SPARC-null and WT mice showed no differences in percent area of invasion or collagenous ECM. Moreover, sponges from old SPARC-null and WT mice contained similar levels of VEGF that were significantly lower than those from young (4-6 months) mice. In contrast to fibroblasts from young SPARC-null mice, dermal fibroblasts from old SPARC-null mice did not migrate farther, proliferate faster, or produce greater amounts of VEGF relative to their old WT counterparts. However, when stimulated with TGF-beta1, primary cells isolated from the sponge implants, and dermal fibroblasts from both old SPARC-null and WT mice, showed marked increases in VEGF secretion. These data indicate that aging results in a loss of enhanced angiogenesis in SPARC-null mice, as a result of the detrimental impact of age on cellular functions, collagen deposition, and VEGF synthesis. However, the influence of aging on these processes may be reversed, in part, by growth factor stimulation.