NO-independent cGMP regulation of vascular remodeling

血管平滑肌(VSM)环鸟苷3‘，5’-环磷酸(CGMP)是一种重要的 许多细胞功能的调节器，有助于损伤后血管的生长。一氧化氮(NO)和 一氧化碳(CO)作为可溶性鸟苷环化酶(SGC)的激活配体参与cGMP的合成； 然而，NO和CO信号的局限性需要对交替的、病理生理学相关的研究 CGMP控制的路线。挑衅性的新发现挑战了cGMP发挥作用的传统观念 通过cGMP依赖的蛋白激酶类型(CGKI)保护血管，并提示cGMP可能 通过cAMP/CAK进行操作以促进血管保护。我们实验室目前的研究重点是新的非独立的 CGMP控制作为重要的基础科学工具和潜在的心血管疾病的方法 治疗学。初步数据支持NO-独立的cGMP和cGMP在血管生长控制中的作用 提示基质金属蛋白酶(MMP2)和MMP9的参与机制。长期目标 本研究项目的目的是研究cGMP对VSM生长的控制策略，并以此为中心 这一提议的假设是，没有独立的cGMP可以防止血管生长，而且这 通过CAK信号发生。两个具体的目标将被用来检验这一假设： 目的1将分析NO不依赖的cGMP和cGMP介导的cGKI/CAK信号转导通路在 减轻大鼠球囊损伤和小鼠钢丝剥脱损伤模型中的血管重塑。 Aim 2将研究基于基质的机制，包括细胞迁移和基质金属蛋白酶平衡 CGMP介导的大鼠和小鼠原代VSM细胞的生长控制。 将使用药理学、RNA干扰和病毒基因传递方法，并有条件地针对VSM 缺乏cGKI的模型将允许直接比较cGKI和CAK机制。结果是 预期为非独立的cGMP控制损伤提供洞察和进一步的证据 VSM中的生长反应以及cGMP导向的MMP在调节这些事件中的作用。 心脏和血管损伤和疾病的范围很广，而且公共卫生非常严重 令人担忧的是，统计数据显示，它们仍然是美国人口死亡的主要原因。我们相信 这些研究的结果将阐明一些新的和有希望的策略，这些策略可以用于 将血管损伤和疾病的严重程度降至最低，并可能为进一步研究提供有益的前景 在基础科学研究和以人为本的临床研究中。

Vascular smooth muscle (VSM) cyclic guanosine 3',5'-moriophosphate (cGMP) serves as a critical regulator of many cellular functions that contribute to vessel growth after injury. Nitric oxide (NO) and carbon monoxide (CO) operate as soluble guanylate cyclase (sGC)-activating ligands for cGMP synthesis; however, limitations of NO and CO signaling warrant study into alternate, pathophysiologically relevant routes for cGMP control. Provocative new findings challenge the traditional notion that cGMP exerts vascular protection through cGMP-dependent protein kinase type (cGKI) and suggest that cGMP may operate via cAMP/cAK to promote vascular protection. Current studies in our laboratory focus on novel NOindependent approaches for cGMP control as significant basic science tools and as potential cardiovascular therapeutics. Preliminary data support a role for vascular growth control by NO-independent cGMP and suggest mechanistic involvement of matrix metalloproteinase (MMP)-2 and MMP-9. The long-term objective of this research project is to investigate strategies for cGMP control of VSM growth, and the central hypothesis of this proposal is that NO-independent cGMP protects against vascular growth and that this occurs through cAK signals. Two Specific Aims will be used to test this hypothesis: Aim 1 will analyze the roles of NO-independent cGMP and cGMP-directed cGKI/cAK signaling in attenuating vascular remodeling in the rat balloon injury and mouse wire denudation injury models. Aim 2 will examine matrix-based mechanisms including cell migration and MMP balance that underlie cGMP-mediated growth control in rat and mouse primary VSM cells. Pharmacology, RNA interference, and viral gene delivery approaches will be used, and conditional VSMspecific cGKI-deficient models will allow direct comparison of cGKI versus cAK mechanisms. Results are anticipated to provide insight into and further evidence for NO-independent cGMP control of the injury growth response in VSM and shed light upon cGMP-directed MMPs in mediating these events. Injuries and diseases of the heart and blood vessels are wide-ranging and very serious public health concerns, and statistics show they are still the major cause of death in American populations. We believe that results from these studies will shed light on some novel and promising strategies that could be used to minimize the severity of blood vessel injury and disease and may offer beneficial prospects for further study in basic science research and human-based clinical studies.