cAMP signaling in vascular smooth muscle in health and disease

抽象的。 第二信使3‘，5’-环磷酸腺苷(CAMP)对血管的调节是必不可少的 平滑肌(VSM)功能，包括反应性。VSM中CAMP信号的教条只是调解 最近，我们观察到葡萄糖诱导了一种微妙的cAMP合成，这对松弛提出了挑战 促进收缩。这些结果表明，cAMP的多功能性调节VSM对不同刺激的反应 取决于它们在细胞内的空间受限属性，而这一点我们知之甚少。此外，没有研究表明 研究了生物性别如何调节cAMP池及其在VSM中对健康和 疾病。因此，这里的研究将解决这些关键的知识差距。通过利用复杂的 工具包在人和鼠的VSM中，令人兴奋的初步数据被生成，以支持以下中心假设 不同cAMP池的产生对于整合受体依赖的cAMP信号控制是必不可少的 VSM在健康和疾病中的反应性，这取决于生物性别。这一假设将在#年进行检验。 三个具体目标。目标1是检验Gs蛋白偶联受体(GsPCRs)诱导性行为的假设。 VSM中的特定离散营地池。目标2是检验GsPCRs细胞分离触发的假设 VSM的不同性别的离散营地池。最后，目标3是检验离散阵营的假设 糖尿病和高血压(HTN)时，VSM中的池被破坏。该提案具有较高的基础性、翻译性和 临床意义，因为它将揭示1)对VSM离散cAMP池的新见解，2)生物学影响 性与健康和疾病，以及3)发现新的目标和开发新的治疗策略的机会。

Abstract . The second messenger 3',5'-cyclic adenosine monophosphate (cAMP) is essential for regulating vascular smooth muscle (VSM) function, including reactivity. The dogma that cAMP signaling in VSM only mediates relaxation was recently challenged by our observation that glucose induces a subtle cAMP synthesis that promotes contraction. These results suggest that cAMP versatility to regulate VSM reactivity to diverse stimuli depends on their spatially confined properties within the cell, of which little is known. Moreover, no studies have examined how cAMP pools are modulated by biological sex and its functional implications in VSM in health and disease. Studies here will therefore address these key knowledge gaps. By leveraging the use of a sophisticated toolkit in human and mouse VSM, exciting preliminary data is generated in support of the central hypothesis that the production of discrete cAMP pools is essential for integrating receptor-dependent cAMP signaling to control VSM reactivity in health and disease, and this is dependent on biological sex. This hypothesis will be tested in three specific aims. Aim 1 is to test the hypothesis that Gs protein-coupled receptors (GsPCRs) induce sex- specific discrete cAMP pools in VSM. Aim 2 is to test the hypothesis that GsPCRs cellular segregation triggers distinct sex-specific discrete cAMP pools in VSM. Finally, Aim 3 is to test the hypothesis that discrete cAMP pools in VSM are disrupted in diabetes and hypertension (HTN). The proposal has high basic, translational and clinical significance as it will reveal 1) new insight into discrete cAMP pools in VSM, 2) their influence by biological sex in health and disease, and 3) opportunities to identify novel targets and develop new therapeutic strategies.