NO-independent cGMP regulation of vascular remodeling

血管平滑肌（VSM）环鸟苷3 '，5'-moriophosphate（cGMP）作为一种关键的 它是许多细胞功能的调节剂，有助于损伤后血管生长。一氧化氮（NO）和 一氧化碳（CO）作为可溶性鸟苷酸环化酶（sGC）活化配体用于cGMP合成; 然而，NO和CO信号传导的局限性保证了对替代的、病理生理学相关的研究， cGMP控制路线。新发现挑战了cGMP发挥作用的传统观念 通过cGMP依赖性蛋白激酶型（cGKI）的血管保护作用，并表明cGMP可能 通过cAMP/cAK起作用，促进血管保护。本实验室目前的研究主要集中在新的NO非依赖性 cGMP控制方法作为重要的基础科学工具和潜在的心血管 治疗学初步数据支持NO-非依赖性cGMP对血管生长的控制作用， 提示基质金属蛋白酶（MMP）-2和MMP-9机制参与。长期目标 本研究项目的主要目的是研究cGMP控制VSM生长的策略， 该建议的假设是NO非依赖性cGMP保护血管生长， 通过cAK信号发生。将使用两个特定目标来检验这一假设： 目的1将分析NO非依赖性cGMP和cGMP指导的cGKI/cAK信号转导在 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。 目的2将研究基质为基础的机制，包括细胞迁移和基质金属蛋白酶的平衡， 大鼠和小鼠原代VSM细胞中cGMP介导的生长控制。 将使用药理学、RNA干扰和病毒基因递送方法，并将使用条件性VSM特异性 cGKI缺陷模型将允许直接比较cGKI与cAK机制。结果 预期为NO非依赖性cGMP控制损伤提供深入了解和进一步证据 VSM的生长反应，并阐明cGMP介导的MMPs介导这些事件。 心脏和血管的损伤和疾病是一种广泛而严重的公共卫生问题 统计数据显示，它们仍然是美国人口死亡的主要原因。我们认为 这些研究的结果将揭示一些新的和有前途的战略，可用于 最大限度地减少血管损伤和疾病的严重程度，并可能为进一步研究提供有益的前景 在基础科学研究和基于人类的临床研究中。

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.