Role of smooth muscle cGMP/cGKI signaling in murine vascular restenosis
Role of smooth muscle cGMP/cGKI signaling in murine vascular restenosis
复制标题
DOI：
10.1161/atvbaha.108.166405
复制
发表时间：
2008-07-01
影响因子：
8.7
通讯作者：
Feil, Robert
中科院分区：
文献类型：
--
作者：
Lukowski, Robert;Weinmeister, Pascal;Feil, Robert
背景：一氧化氮（NO）对平滑肌细胞（SMC）的功能起着至关重要的作用，对血管再狭窄有许多甚至相反的作用。尽管cgmp依赖性蛋白激酶I型（cGKI）是NO的主要效应因子，但血管NO信号在再狭窄中的分子通路尚不清楚。本研究旨在探讨平滑肌cGMP/cGKI信号级联在血管再狭窄中的功能作用。方法与结果：在SMCs中消融cGKI蛋白，生成组织特异性小鼠突变体。我们研究了在颈动脉结扎或内皮去除后，SMCs中cGKI的缺失是否会影响血管重构。在正常血脂或apoe缺乏的背景下，在血管损伤后的不同时间点，组织特异性cGKI突变体和对照小鼠之间没有发现差异。与这些结果一致，用磷酸二酯酶-5抑制剂西地那非慢性药物治疗损伤对照小鼠，cGMP水平升高，但对结扎诱导的重塑没有影响。结论cGMP/cGKI信号通路的遗传和药理学操作表明该通路不参与NO的保护作用，提示NO通过其他机制影响再狭窄过程中的血管重构。
Background-Nitric oxide (NO) is of crucial importance for smooth muscle cell (SMC) function and exerts numerous, and sometimes opposing, effects on vascular restenosis. Although cGMP-dependent protein kinase type I (cGKI) is a principal effector of NO, the molecular pathway of vascular NO signaling in restenosis is unclear. The purpose of this study was to examine the functional role of the smooth muscle cGMP/cGKI signaling cascade in restenosis of vessels.Methods and Results-Tissue-specific mouse mutants were generated in which the cGKI protein was ablated in SMCs. We investigated whether the absence of cGKI in SMCs would affect vascular remodeling after carotid ligation or removal of the endothelium. No differences were detected between the tissue-specific cGKI mutants and control mice at different time points after vascular injury on a normolipidemic or apoE-deficient background. In line with these results, chronic drug treatment of injured control mice with the phosphodiesterase-5 inhibitor sildenafil elevated cGMP levels but had no influence on the ligation-induced remodeling.Conclusions-The genetic and pharmacological manipulation of the cGMP/cGKI signaling indicates that this pathway is not involved in the protective effects of NO, suggesting that NO affects vascular remodeling during restenosis via alternative mechanisms.