Arcot S S, Lipke D W, Gillespie M N, Olson J W
University of Kentucky A.B. Chandler Medical Center, College of Pharmacy, Division of Pharmacology and Experimental Therapeutics, Lexington 40536-0082.
Biochem Pharmacol. 1993 Sep 14;46(6):1086-91. doi: 10.1016/0006-2952(93)90675-m.
Although pathologic and hemodynamic changes in monocrotaline (MCT)-induced pulmonary hypertension have been studied extensively, relatively little is known about the inter- and intracellular signaling mechanisms underlying such alterations. As a first step to delineating signaling mechanisms governing adverse structural alterations in the hypertensive lungs, we examined changes in the steady-state levels of mRNAs encoding several growth factors including transforming growth factors (TGF), platelet-derived growth factors (PDGF), vascular endothelial cell growth factor (VEGF) and endothelin (ET) as a function of time in MCT-induced pulmonary hypertension in rats. These studies demonstrated a very diverse pattern of growth factor gene expression in response to MCT administration. In general, alterations in the steady-state levels of mRNAs encoding the growth factors preceded the onset of MCT-induced pulmonary hypertension. TGF-beta 1, -beta 2 and -beta 3 transcripts were seen to be elevated, whereas that of TGF-alpha and PDGF-A remained unchanged. Transcripts for PDGF-B and ET were increased in the early stages but declined to less than controls in the latter stages of MCT-induced hypertension. In contrast, levels of VEGF mRNA decreased to less than controls as the disease progressed. Viewed collectively, the diverse pattern of expression suggests that alterations in the levels of the growth factor transcripts may have a significant role in the development of pulmonary hypertensive disease and may be relevant to the pathological and structural changes in MCT-induced pulmonary hypertension.
尽管对野百合碱（MCT）诱导的肺动脉高压中的病理和血流动力学变化已进行了广泛研究，但对于这种改变背后的细胞间和细胞内信号传导机制却知之甚少。作为描绘高血压肺脏中不良结构改变的信号传导机制的第一步，我们研究了在MCT诱导的大鼠肺动脉高压中，作为时间函数的几种生长因子（包括转化生长因子（TGF）、血小板衍生生长因子（PDGF）、血管内皮细胞生长因子（VEGF）和内皮素（ET））编码mRNA的稳态水平变化。这些研究表明，对MCT给药的反应中生长因子基因表达模式非常多样。一般来说，编码生长因子的mRNA稳态水平的改变先于MCT诱导的肺动脉高压的发生。观察到TGF-β1、-β2和-β3转录本升高，而TGF-α和PDGF-A的转录本保持不变。PDGF-B和ET的转录本在早期升高，但在MCT诱导的高血压后期降至低于对照水平。相反，随着疾病进展，VEGF mRNA水平降至低于对照水平。总体来看，这种多样的表达模式表明，生长因子转录本水平的改变可能在肺动脉高压疾病的发展中起重要作用，并且可能与MCT诱导的肺动脉高压中的病理和结构变化相关。
