Transforming Growth Factor-Beta-Dependent Events in Vascular Remodeling following Arterial Injury

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Abstract

Constrictive remodeling has been identified as a major contributor to restenosis following angioplasty. Characterization of transforming growth factor-β (TGF-β)-mediated cellular events in the adventitia and their contribution to vascular remodeling, however, has not previously been studied in detail. The balloon catheter denudation model was performed on rat carotid artery, and groups of rats were treated with vehicle or a TGF-β inhibitor, a soluble TGF-β receptor type II (TGF-βR:Fc). Adventitial cell proliferation, which peaked 4 days after injury, was characterized by the de novo formation of several cell layers surrounding the outer adventitia and this process was not dependent upon TGF-β activity. These neoadventitial cells expressed an abundance of collagen type I and a fetal isoform of fibronectin containing the EIIIA domain, and the expression of both proteins was suppressed in the presence of TGF-βR:Fc. Lumenal narrowing was apparent 14 days after injury. Inhibition of TGF-β signaling promoted vessel enlargement. As a result, lumen size did not change despite neointima formation. In conclusion, adventitial fibrosis with abundant collagen matrix deposition but not adventitial cell proliferation is dependent upon endogenous TGF-β activity. Furthermore, inhibition of TGF-β signaling prevents injury-induced reduction in lumen area by promoting vessel enlargement.

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Proliferative activity and alpha-smooth muscle actin expression in cultured rat aortic smooth muscle cells are differently modulated by transforming growth factor-beta 1 and heparin.

Palmer A. Orlandi, G Gabbiani, P Ropraz (1994)

Locally liberated cytokines and extracellular matrix components influence the proliferation and differentiation of arterial smooth muscle cells (SMC), thus playing a role in the development of the atheromatous plaque. It has been proposed that the response of SMC to these factors is influenced by their own phenotype. We have tested the effects of transforming growth factor-beta 1 (TGF-beta 1) and heparin on proliferation and expression of alpha-smooth muscle (SM) actin, a well-established SMC differentiation marker, by cultured rat SMC obtained from the normal aorta of young or old rats and from the intimal thickening developed 15 days after endothelial denudation in young rats; these SMC are known to express different phenotypic features. Heparin and TGF-beta 1 reduced serum-induced proliferation in SMC from young and old rats. Heparin increased the expression of alpha-SM actin protein and mRNA in SMC from young and old rats, while TGF-beta 1 exerted the opposite action. Moreover, TGF-beta 1 induced the appearance of an elongated shape in SMC from both young and old rats. In SMC cultured from intimal thickening, heparin induced a reduction of cell proliferation without modifying their characteristic epithelioid shape; TGF-beta 1 increased the proliferative activity and induced an elongated cell shape as well as a "hills and valleys" growth pattern similar to that observed in control medial SMC; both heparin and TGF-beta 1 induced an increase of alpha-SM actin expression. Our results show that TGF-beta 1 and heparin exert different effects on the same SMC, suggesting that these substances act at least in part independently. They are also compatible with the view that the action of cytokines and of extracellular matrix components depends on the phenotype of target SMC.