Role of transforming growth factor-beta 1 in the cellular growth response to angiotensin II.

Abstract

We have shown that angiotensin II (Ang II)-induced hypertrophy of vascular smooth muscle cells is dependent on the balance between proliferatlve and antlproliferative growth factors, specifically basic fibroblast growth factor and transforming growth factor-/31 (TGF-01), respectively. We now present evidence, based on two phenotypically distinct cell cultures, that the ability to secrete the biologically active form of TGF-/31 is central to the growth response to Ang II. Two separate cultures were examined, one in which Ang II induces hypertrophy and the other in which Ang II induces hyperplasia. Ang II induces the expression of basic fibroblast growth factor twofold to fivefold in both cultures. Furthermore, both cultures express TGF-/J1. In the culture that responds with hypertrophy, Ang II induces the expression of the active form of TGF-/31 twofold to threefold. However, in the culture that responds with hyperplasia, no active TGF-/J1 was detected either at baseline or after Ang II exposure. Interestingly, all the TGF-01 present was in the inactive, latent form. In the culture that responded with hyperplasia, Ang II induced a fourfold to fivefold increase in DNA synthesis. This increase could be abolished by the addition of active TGF-01. Thus in these two cultures the ability to activate TGF-01 dictates the cellular response to Ang II. These results support our hypothesis that a balance of proliferative and antiproliferative autocrine signals mediates the growth control of vascular smooth muscle cells. 1 For example, hypertension results in vascular hypertrophy that in large conduit vessels, is due primarily to cellular hypertrophy, 2 whereas in resistance arteries hyperplasia predominates.3 In atherosclerosis, vascular smooth muscle proliferation within the intima is a major cause of plaque formation.1 Moreover, the vascular response to injury after mechanical trauma such as balloon angioplasty 4 also involves smooth muscle proliferation. The understanding of the mechanisms behind abnormal, uncontrolled proliferation is central to attempts to inhibit or control lesion formation.Among the factors responsible for the regulation of vascular smooth muscle growth, vasoactive substances play a major role. Angiotensin II (Ang II) has been used as a paradigm for these studies. In vivo, angiotensin converting enzyme (ACE) inhibitors attenuate the development of hypertension-induced vascular hypertro-

The expression of transforming growth factor β in pregnant rat myometrium is hormone and stretch dependent

“…Arici and colleagues demonstrated that low concentrations of TGFb1 stimulate cell proliferation in leiomyoma (Arici & Sozen 2003) and vascular cells (Battegay et al 1990), while these stimulatory effects disappear at high TGFb1 concentrations. It has been also shown that increased TGFb1 gene expression induced by angiotensin II led to de novo protein synthesis in cultured vascular SMC (Koibuchi et al 1993). New protein synthesis is a property of hypertrophic cells.…”

Vascular Remodeling in Hypertension

“…36 -38 These effects may depend on the antifibrotic actions of these agents that downregulate the expression of transforming growth factor-␤ (TGF-␤). Indeed, this has been well demonstrated for Ang II, which exerts its growth 39 and profibrotic effects 40 in part via stimulation of TGF-␤, suggesting that at least ACEIs and ARBs, by inhibiting Ang II generation or blocking its action, may affect stiffness partly through this mechanism. Reduction of small artery stiffness decreases impedance, which delays wave reflection and consequently the augmentation of pulse pressure centrally in the aorta.…”

Modulation of Reactive Oxygen Species and Collagen Synthesis by Angiotensin II in Cardiac Fibroblasts

“…Indeed, cardiac fibroblasts are the principal cellular origin of TGF-β 1 and in cultured rat adult cardiac fibroblasts ANG II stimulates TGF-β 1 gene expression, increases total TGF-β 1 production and promotes the conversion of latent TGF-β 1 to the active form [50,[55][56][57][58][59]. Simultaneous treatment of cardiac fibroblasts in vitro with ANG II and a neutralizing antibody to TGF-β 1 reduces type I and type III collagen mRNA expression [59] and collagen production ( Fig.…”