Department of Pharmacology, University of South Alabama College of Medicine, Mobile, AL, 36688, USA.
Adv Exp Med Biol. 2010;661:299-308. doi: 10.1007/978-1-60761-500-2_19.
Rho kinase-mediated vasoconstriction rather than fixed arterial wall thickening is responsible for increased pulmonary vascular resistance and pulmonary hypertension in chronically hypoxic and monocrotaline-injected rats. In the absence of vascular tone, the medial and adventitial thickening in these models has only minimal impact on the cross-sectional area of the pulmonary arterial bed. In contrast, increased pulmonary vascular resistance in left-pneumonectomized plus monocrotaline-injected rats and VEGF receptor blocker-injected plus chronic hypoxia rats is attributable to both Rho kinase-mediated vasoconstriction and formation of lumen obliterating lesions in small pulmonary arteries. The upstream signals responsible for activation of RhoA/Rho kinase signaling in hypertensive pulmonary arteries and whether or not they differ in different forms of pulmonary hypertension are unclear. The RhoA/Rho kinase pathway is a convergence point of several different vasoconstrictor signals, including those mediated by G protein-coupled receptors, receptor tyrosine kinases, and integrin clustering. Both isoforms of Rho kinase can also be constitutively activated by cleavage, and cleaved Rho kinase 1 has been detected in the hypertensive lungs of left-pneumonectomized plus monocrotaline-injected rats. That such diverse stimuli can lead to activation of Rho kinase, which may cause hypercontraction of smooth muscle by promoting both actomyosin interaction and remodeling of the cytoskeleton, may explain why in various rat models of pulmonary hypertension Rho kinase inhibitors are more effective pulmonary vasodilators than conventional agents such as nitric oxide, prostacyclin, and nifedipine. We suspect the same will be true in at least some forms of human pulmonary arterial hypertension.
Rho 激酶介导的血管收缩而非固定的动脉壁增厚是导致慢性低氧和单克隆鼠尾草注射大鼠肺血管阻力和肺动脉高压增加的原因。在没有血管张力的情况下，这些模型中的中膜和外膜增厚对肺小动脉床的横截面积仅有最小的影响。相比之下，左肺切除加单克隆鼠尾草注射大鼠和血管内皮生长因子受体阻滞剂注射加慢性低氧大鼠的肺血管阻力增加归因于 Rho 激酶介导的血管收缩和小肺动脉管腔闭塞病变的形成。导致高血压肺血管中 RhoA/Rho 激酶信号转导激活的上游信号以及它们在不同形式的肺动脉高压中是否不同尚不清楚。RhoA/Rho 激酶通路是几种不同血管收缩信号的汇聚点，包括 G 蛋白偶联受体、受体酪氨酸激酶和整合素聚类介导的信号。两种 Rho 激酶同工型也可以通过切割被组成型激活，并且在左肺切除加单克隆鼠尾草注射大鼠的高血压肺中已经检测到切割的 Rho 激酶 1。这种多样性的刺激可以导致 Rho 激酶的激活，这可能通过促进肌球蛋白相互作用和细胞骨架重塑来导致平滑肌过度收缩，这可能解释为什么在各种大鼠肺动脉高压模型中，Rho 激酶抑制剂比传统药物如一氧化氮、前列环素和硝苯地平更有效地扩张肺血管。我们怀疑在至少一些形式的人类肺动脉高压中也是如此。
