Zou Y, Hu Y, Metzler B, Xu Q
Institute for Biomedical Aging Research, Austrian Academy of Sciences, Innsbruck, Austria.
Int J Mol Med. 1998 May;1(5):827-34. doi: 10.3892/ijmm.1.5.827.
Vascular smooth muscle cell (SMC) proliferation is a key event in the development of (spontaneous) atherosclerosis, hypertension-related arteriosclerosis, angioplasty-induced restenosis and venous bypass graft arteriosclerosis. Many factors or environmental stimuli are believed to be responsible for SMC growth or hypertrophy in the vessel wall. How these environmental stimuli or signals applied onto the surface of SMCs are transduced into the cell nucleus resulting in quantitative and qualitative changes in gene expression in SMCs of arterial walls is largely unknown. Mitogen-activated protein (MAP) kinases are rapidly activated in cells stimulated with various extracellular signals by dual phosphorylation of tyrosine and threonine residues. They are thought to play a pivotal role in transmitting transmembrane signals required for cell growth and differentiation. Recent studies have focused on the signalling events in vascular tissues in vivo and in cultured SMCs in vitro. It has been demonstrated that acute hypertension and angioplasty rapidly induced MAP kinase activation in the arterial wall. Kinase activation is followed by an increase in c-fos and c-jun gene expression and enhanced transcription factor AP-1 DNA-binding activity. A similar MAP kinase activation can be mimicked in in vitro cultured SMCs stimulated by either shear stress or cyclic strain stretch, suggesting direct effects of mechanical force. Interestingly, physical forces rapidly resulted in phosphorylation of platelet-derived growth factor (PDGF) receptor, an activated state, in cultured SMCs. Thus, mechanical stresses may directly perturb the cell surface or alter receptor conformation, thereby initiating signalling pathways usually used by growth factors. These findings have significantly enhanced our knowledge concerning the pathogenesis of arteriosclerosis and provide a basis for therapeutic intervention on vascular diseases.
血管平滑肌细胞（SMC）增殖是（自发性）动脉粥样硬化、高血压相关动脉硬化、血管成形术诱导的再狭窄和静脉搭桥移植动脉硬化发展过程中的关键事件。许多因素或环境刺激被认为与血管壁中SMC的生长或肥大有关。这些施加在SMC表面的环境刺激或信号如何转导至细胞核，从而导致动脉壁SMC中基因表达在数量和质量上发生变化，目前尚不清楚。丝裂原活化蛋白（MAP）激酶在受到各种细胞外信号刺激的细胞中，通过酪氨酸和苏氨酸残基的双重磷酸化而迅速被激活。它们被认为在传递细胞生长和分化所需的跨膜信号中起关键作用。最近的研究集中在体内血管组织和体外培养的SMC中的信号转导事件。已经证明，急性高血压和血管成形术可迅速诱导动脉壁中的MAP激酶激活。激酶激活之后是c-fos和c-jun基因表达增加以及转录因子AP-1 DNA结合活性增强。在体外培养的SMC中，通过剪切应力或循环应变拉伸刺激，可模拟类似的MAP激酶激活，这表明机械力具有直接作用。有趣的是，物理力可迅速导致培养的SMC中血小板衍生生长因子（PDGF）受体磷酸化，使其处于激活状态。因此，机械应力可能直接干扰细胞表面或改变受体构象，从而启动通常由生长因子使用的信号通路。这些发现显著增强了我们对动脉硬化发病机制的认识，并为血管疾病的治疗干预提供了依据。
