Itoh H, Mukoyama M, Pratt R E, Gibbons G H, Dzau V J
Falk Cardiovascular Research Center, Stanford University School of Medicine, California 94305-5246.
J Clin Invest. 1993 May;91(5):2268-74. doi: 10.1172/JCI116454.
Angiotensin (Ang) II stimulates hypertrophic growth of vascular smooth muscle cells (VSMC). Accompanying this growth is the induction of the expression of growth-related protooncogenes (c-fos, c-jun, and c-myc), as well as the synthesis of the autocrine growth factors, such as PDGF-A and TGF-beta 1. In this study, we demonstrate further that Ang II also induces the synthesis of basic fibroblast growth factor (bFGF), a potent mitogen for VSMC. To examine how these factors interact to modulate the growth response of VSMC to Ang II, we used antisense oligomers to determine the relative contribution of these three factors. Treatment of confluent, quiescent smooth muscle cells with specific antisense oligomers complementary to bFGF, PDGF-A, and TGF-beta 1 efficiently inhibited the syntheses of these factors. Our results demonstrate that in these VSMC, TGF-beta 1 affects a key antiproliferative action, modulating the mitogenic properties of bFGF. Autocrine PDGF exerts only a minimal effect on DNA synthesis. An imbalance in these signals activated by Ang II may result in abnormal VSMC growth leading to the development of vascular disease.
血管紧张素（Ang）II 刺激血管平滑肌细胞（VSMC）的肥大生长。伴随这种生长的是生长相关原癌基因（c-fos、c-jun 和 c-myc）表达的诱导，以及自分泌生长因子如血小板衍生生长因子 A（PDGF-A）和转化生长因子β1（TGF-β1）的合成。在本研究中，我们进一步证明 Ang II 还诱导碱性成纤维细胞生长因子（bFGF）的合成，bFGF 是一种对 VSMC 有强大作用的促有丝分裂原。为了研究这些因子如何相互作用以调节 VSMC 对 Ang II 的生长反应，我们使用反义寡核苷酸来确定这三种因子的相对贡献。用与 bFGF、PDGF-A 和 TGF-β1 互补的特异性反义寡核苷酸处理汇合的静止平滑肌细胞，有效抑制了这些因子的合成。我们的结果表明，在这些 VSMC 中，TGF-β1 影响关键的抗增殖作用，调节 bFGF 的促有丝分裂特性。自分泌的 PDGF 对 DNA 合成仅产生最小的影响。由 Ang II 激活的这些信号失衡可能导致 VSMC 异常生长，从而导致血管疾病的发生。
