Effects of transforming growth factor-beta 1 on human arterial smooth muscle cells in vitro.

Abstract

Control of the thickness of the arterial wall is critical, as excessive overgrowth of constituent smooth muscle cells (SMCs) may interfere with blood flow. Effects on SMCs in vitro of several growth factors that are present in blood and/or that are produced endogenously in the arterial wall under certain conditions suggest that influences of endocrine, paracrine, and autocrine nature from stimulating and inhibiting factors may control the smooth muscle tissue mass in the artery. This possibility was explored further by investigating the degree of myodifferentiation in terms of the presence of differentiation-specific filamentous a-smooth muscle actin and growth, as measured by the synthesis of DNA and cell number, of SMCs as influenced by their exposure to the mitogens, platelet-derived growth factor and epidermal growth factor, and the bifunctional growth factor, transforming growth factor-01 (TGF-/31). Exposure to TGF-/31 markedly enhanced differentiation-specific filamentous o-smooth muscle actin. This effect did not require arrest of growth, which speaks against a direct causal relation between loss of myodifferentiation (modulation) and multiplication. When quiescent cultures were exposed to TGF-/31, <*-smooth muscle actin was further increased, indicating a more specific differentiation-promoting effect by TGF-/31 than mere inhibition of growth. Exposure to TGF-/31 also increased spreading, which occurred in parallel with increased filamentous tv-smooth muscle actin and appearance of stress fibers. Exposure to platelet-derived growth factor under serum-free conditions and to epidermal growth factor in cultures exposed to serum markedly decreased the number of cv-actin-positive SMCs, indicating a dedifferentiating effect by these mitogens. Exposure of SMCs to TGF-/31 under serum-free conditions had pronounced effects on growth, with a concentration-dependent inhibition of platelet-derived growth factor-induced DNA synthesis and cell multiplication. The basal synthesis of DNA in the absence of added growth factors was also greatly inhibited. With serum-free cultures, some loss of cells occurred even with very low concentrations of TGF-/31 (5 pg/ml), against which platelet-derived growth factor or a dense cultural state had a protective effect. Enhancement of cell multiplication was not detected for cultivated human SMCs exposed to TGF-/31, irrespective of culture density, in contrast to that reported for dense cultures of rat SMCs. TGF-/31 is present in and may be released from platelets in situations that promote platelet adherence such as endothelial injury; TGF-/31 may also be released from activated macrophages and T lymphocytes either during an immune reaction or inflammation or from the endothelium. The pronounced effects in vitro of this factor with promotion of myodifferentiation and inhibition of growth of SMCs could be consistent with a role for this factor of regulation of SMC growth and myodifferentiation in the arterial wall normally, during inflammation, and in atherosclerosis. (Arteriosclerosi...

Transforming growth factor (TGF)-β levels and unprovoked recurrent venous thromboembolism

“…Cell culture studies suggest that TGF-β protects against atherosclerosis by inhibiting the proliferation of vascular smooth muscle cells [21,22]. Preclinical studies also indicate a protective role for TGF-β1 in atherogenesis.…”

Distribution of transforming growth factor-beta 1, fibronectin, and smooth muscle actin in asbestos-induced pulmonary fibrosis in rats.

“…It is clear that TGFP and other factors can affect contractile cells and proteins in a variety of cell types (Mitchell et al, 1993). TGFP has been shown to up-regulate a-smooth muscle actin in cardiac myocytes (Parker et al, 1990) and smooth muscle cells (Bjorkerud, 1991) but not in fibroblasts (Rubbia-Brandt et al, 1991). It is feasible that the local increase in smooth muscle actin found at first alveolar duct bifurcations could be a result of paracrine stimulation by the E F P produced by alveolar macrophages accumulating on the surfaces of the bifurcations.…”

“…In addition to stimulation of extracellular matrix production, TGFD stimulates proliferation of certain types of mesenchymal cells (Moses et al, 1987) and can be chemotactic for fibroblasts (Roberts and Spom, 1990). TGFB also enhances the expression of a-smooth muscle actin in cultured myocytes and smooth muscle cells (Bjorkerud, 1991;Parker et al, 1990). Expression of a-smooth muscle actin increases in bleomycin-induced fibrosis of rat lung (Mitchell et al, 1989).…”

Regulation of Discoidin Domain Receptor 2 by Cyclic Mechanical Stretch in Cultured Rat Vascular Smooth Muscle Cells

“…11 Transforming growth factor-␤ (TGF-␤) plays an important role in maintaining normal vessel wall structure, and that loss of this protective effect contributes to the development of atherosclerosis. 12 TGF-␤ inhibits smooth muscle proliferation, [13][14][15] inhibits VSMC migration, 16 and promotes the expression of an array of proteins that make up the contractile apparatus of the cell. [13][14][15][16] Reduced TGF-␤ activity is a common consequence of a range of environmental and genetic factors associated with development of atherosclerosis.…”