Title

Evidence for an age-related dysfunction in the antiproliferative response to transforming growth factor-β in vascular smooth muscle cells

Document Type

Journal Article

Publication Date

1-1-1993

Journal

Molecular Biology of the Cell

Volume

4

Issue

3

DOI

10.1091/mbc.4.3.315

Abstract

Previous studies have indicated that aged animals show an increased intimal hyperplasia after arterial injury. The present studies examined the hypothesis that the increased serum-free proliferation of aged smooth muscle cells (SMC), in vitro, was due to a loss of an antiproliferative signal, such as transforming growth factor-β (TGF-β1). Northern blot analysis of the mRNA derived from old (> 19 mo) or young (3-4 mo) rat aortic SMC indicated that both groups had an equivalent level of the 2.5 kB TGF-β1message. Metabolic labeling with 35S-methionine and immunoprecipitation for TGF-β1 confirmed the de novo synthesis of TGF-β1 in rat SMC. Old and young SMC supernatants showed equal levels of active or latent (acid-activated) TGF-β activity. Despite the similarities in the production of TGF-β1, old SMC were refractory to inhibition by TGF-β1, whereas young SMC were markedly inhibited (80%) by low levels of TGF-β1 (IC50 < 5 pg/ml). Binding studies at 4°C indicated that old SMC exhibited reduced binding capacity for 125I-TGF-β1.Crosslinking studies confirmed that old SMC showed reduced binding of 125I-TGF-β1 to membrane sites corresponding to the high molecular weight type III receptor, as well as the 85-kDa type II and 65-kDa type I receptor. However, at 37°C, old SMC degraded 125I-TGF-β1 more rapidly than young SMC. Combined, this data suggests that SMC derived from older animals are capable of normal production of TGF-β1 but fail to respond to the autocrine growth inhibitory effects of this agent, thereby leading to enhanced proliferation.

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