Role of endogenous angiotensin II in the increased expression of growth factors in vascular smooth muscle cells from spontaneously hypertensive rats

Abstract

In culture, vascular smooth muscle cells (VSMC) derived from spontaneously hypertensive rats (SHR) show exaggerated growth compared with cells from normotensive Wistar-Kyoto (WKY) rats. SHR-derived VSMC express higher levels of transforming growth factor (TGF)-beta1, platelet-derived growth factor (PDGF) A-chain, and basic fibroblast growth factor (bFGF) mRNAs than cells from WKY rats. We have recently observed production of angiotensin II (Ang II) in homogeneous cultures of VSMC from SHR. In the current study we investigated the contribution of endogenous Ang II to increased expression of the above-mentioned growth factors in VSMC from SHR. The levels of mRNAs encoding TGF-beta1, PDGF A-chain, and bFGF were determined by reverse transcription-polymerase chain reaction and were much higher in VSMC from SHR than in cells from WKY rats. The basal level of Ang II-like immunoreactivity (LI) in conditioned medium as determined by radioimmunoassay was significantly higher in VSMC from SHR than in cells from WKY rats. Isoproterenol is known to induce angiotensinogen gene significantly increased Ang II-LI in VSMC from both WKY rats and SHR. Isoproterenol also increased angiotensinogen, TGF-beta1, PDGF A-chain, and bFGF mRNAs in VSMC from SHR. An angiotensin-converting enzyme inhibitor delapril significantly decreased Ang II-LI in VSMC from WKY rats and SHR. Delapril considerably decreased the levels of TGF-beta1, PDGF A-chain, and bFGF mRNAs in VSMC from SHR. An Ang II type 1 receptor antagonist CV 11974 decreased the levels of TGF-beta1, PDGF A-chain, and bFGF mRNAs, and the levels of TGF-beta1, PDGF-AA, and bFGF proteins in VSMC from SHR. These findings suggest that increased generation of Ang II is associated with enhanced expression of TGF-beta1, PDGF A-chain, and bFGF, and the increases in the levels of these growth factors by endogenous Ang II may contribute to the exaggerated growth of VSMC from SHR.