Transforming Growth Factor-/Jl Gene Activation and Growth of Smooth Muscle From Hypertensive Rats

Cultured vascular smooth muscle cells derived from the spontaneously hypertensive rat (SHR) are known to replicate more rapidly than cells from the normotensive Wistar-Kyoto (WKY) rat. In this study we compared the responses of vascular smooth muscle cells from the two strains to transforming growth factor-01 (TGF-/31) and evaluated its potential to account for the different growth properties of these cells in response to a number of vascular-derived growth factors. TGF-/31 potentiated the proliferative effects of epidermal growth factor, basic fibroblast growth factor, or the different isoforms of platelet-derived growth factor on vascular smooth muscle cells from SHR but inhibited growth factorstimulated proliferation of vascular smooth muscle cells from WKY rats. These differential effects of TGF-01 on proliferation could not be attributed to alterations in the expression of the type I, II, or III TGF-/3 receptors but appeared more Vascular hypertrophy is a major contributor to the increase in vascular resistance in spontaneously hypertensive rats (SHR). In these animals hypertrophy of the resistance vessels is, at least in part, attributed to a greater number of smooth muscle cells within the vessel wall. It has been suggested that differences between the ability of vascular smooth muscle cells (VSMC) from SHR and normotensive WistarKyoto (WKY) rats to respond to the mitogenic influence of vascular-derived growth factors could account for this "proliferative hypertrophy" in genetic hypertension. One of these vascular-derived growth factors, transforming growth factor-^1 (TGF-/31), is a multifunctional protein that regulates the growth and differentiation of a wide variety of cells in culture. In VSMC TGF-/31 can induce both cellular hypertrophy and polyploidy as well as stimulate and/or inhibit proliferation.' For example, TGF-/31 has been shown to stimulate the proliferation of both sparse and dense cultures of human smooth muscle cells." Also, TGF-/31 inhibits serum-stimulated proliferation of rat VSMC, seeded at low densities; at high densities the opposite effect on proliferation is observed. These opposing effects of TGF-01 are elicited after its interaction with multiple receptors on the surface of smooth muscle cells. Received May 13, 1993; accepted in revised form February 9, 1994. From the Baker Medical Research Institute and Alfred Hospital, Prahran, Victoria, Australia. Correspondence to Dr Alex Agrotis, Baker Medical Research Institute, Commercial Rd, Prahran, 3181 Victoria, Australia. related to the ability of cells to autoinduce the TGF-/31 gene. TGF-/31 caused a time-dependent increase in its own mRNA levels in vascular smooth muscle cells of WKY rats but attenuated levels in vascular smooth muscle cells of SHR. This effect was specific to TGF-01 autoinduction since similar elevations in TGF-01 mRNA levels were observed when vascular smooth muscle cells from the two rat strains were exposed to phorbol myristate acetate, basic fibroblast growth factor, or platelet-derived growth factor-BB. These data suggest that the production of TGF-01 may contribute to the different growth properties of vascular smooth muscle cells from SHR and WKY rats through alterations in TGF-/31 signaling systems. (Hypertension. 1994;23:593-599.)