Bray P, Agrotis A, Bobik A
Baker Medical Research Institute, Alfred Hospital, Prahran, Victoria, Australia.
Hypertension. 1998 Apr;31(4):986-94. doi: 10.1161/01.hyp.31.4.986.
Previous studies have suggested that differences in vascular smooth muscle cell (VSMC) proliferative responses between spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto (WKY) rats can be attributed to transforming growth factor-beta (TGF-beta) actions. Because vascular collagen content is reported to be lower in SHR than in WKY rats, in this study we investigated in cell culture whether the differences in collagen content might also be attributed to differential actions of TGF-beta on VSMCs from the two strains. Exposure of VSMCs from WKY to the TGF-beta isoforms -beta1, -beta2, or -beta3 induced rapid, transient elevations in mRNAs encoding collagens alpha1(I), alpha2(I), and alpha1(III); maximum increases were apparent by 2 hours and ranged from twofold [collagen alpha1(III)] to ninefold [collagen alpha1(I)]. Thereafter they returned to near basal levels. When VSMCs from SHR were exposed to these TGF-beta isoforms, only reductions in collagen mRNA levels were observed, persisting for 24 hours. Basic fibroblast growth factor and epidermal growth factor, factors known to stimulate production of the TGF-beta1 isoform in VSMCs, also induced a pattern of gene responses similar to those induced by the TGF-beta isoforms in VSMCs from SHR and WKY rats. The simultaneous presence of TGF-beta did not affect the time course or magnitude of the changes in collagens alpha1(I), alpha2(I), or alpha1(III) mRNA levels in SHR or WKY VSMCs. Examination of the induction of c-myc mRNA and immunoreactive oncoprotein content indicated that c-myc is a likely contributor to the downregulation of the collagen gene activity in both SHR and WKY VSMCs despite the differential regulation of its mRNA by TGF-beta1 in the two VSMC lines. Together these data suggest that in VSMCs from SHR, a number of gene responses to TGF-beta, in addition to cell proliferation, appear to be abnormal compared with WKY rats, and the lower than normal collagen levels observed in the vasculature of SHR may be in part due to abnormalities in TGF-beta responsiveness.
先前的研究表明，自发性高血压大鼠（SHR）与正常血压的Wistar-Kyoto（WKY）大鼠之间血管平滑肌细胞（VSMC）增殖反应的差异可归因于转化生长因子-β（TGF-β）的作用。由于据报道SHR的血管胶原含量低于WKY大鼠，因此在本研究中，我们在细胞培养中研究了胶原含量的差异是否也可归因于TGF-β对这两种品系VSMC的不同作用。将WKY的VSMC暴露于TGF-β同工型-β1、-β2或-β3会导致编码胶原α1（I）、α2（I）和α1（III）的mRNA迅速、短暂升高；2小时时出现最大增加，范围从两倍[胶原α1（III）]到九倍[胶原α1（I）]。此后它们恢复到接近基础水平。当将SHR的VSMC暴露于这些TGF-β同工型时，仅观察到胶原mRNA水平降低，持续24小时。碱性成纤维细胞生长因子和表皮生长因子是已知可刺激VSMC中TGF-β1同工型产生的因子，它们也诱导了与SHR和WKY大鼠VSMC中TGF-β同工型诱导的基因反应模式相似的反应。TGF-β的同时存在不影响SHR或WKY VSMC中胶原α1（I）、α2（I）或α1（III）mRNA水平变化的时间进程或幅度。对c-myc mRNA诱导和免疫反应性癌蛋白含量的检查表明，尽管在两种VSMC系中TGF-β1对其mRNA的调节存在差异，但c-myc可能是SHR和WKY VSMC中胶原基因活性下调的一个因素。这些数据共同表明，在SHR的VSMC中，与WKY大鼠相比，除细胞增殖外，TGF-β的许多基因反应似乎异常，并且在SHR血管中观察到的低于正常的胶原水平可能部分归因于TGF-β反应性异常。
