Local, mast cell-mediated cardiovascular actions of endothelial C-type natriuretic peptide

血管内皮细胞(EC)与邻近的管腔、壁细胞和血管外细胞的旁分泌通讯在心血管内稳态中起着至关重要的作用。内皮细胞功能障碍和与炎性和平滑肌细胞、成纤维细胞和心肌细胞的串扰改变导致血管和心脏疾病，如动脉粥样硬化和高血压或缺血性心脏重塑。在这些旁分泌因子中，内皮衍生的C型利钠肽(CNP)补充了一氧化氮和前列环素的稳态作用。CNP可调节血管阻力，从而降低全身血压，防止微循环炎症、动脉粥样硬化和动脉瘤。产生cGMP的鸟苷酸环化酶B(GC-B)受体在不同的血管和邻近细胞中都有表达。然而，介导这种保护性CNP作用的确切靶细胞和机制尚不清楚。值得注意的是，我们正在进行的体外和体内研究表明，CNP在血管周围驻留肥大细胞(MC)中诱导GC-B/cGMP信号转导。对小鼠提睾肌微循环的活体显微镜研究表明，外源合成的CNP完全阻止了缺血/再灌流诱导的MC脱颗粒和炎症。为了研究内源性内皮CNP是否作为血管周围MC的旁分泌调节剂，我们建立了一种新的GC-B受体有条件的MC限制性缺失的遗传小鼠模型(MC GC-B KO小鼠)。本项目将把MC缺陷、MC报告和MC GC-B KO小鼠的研究与培养MC的研究结合起来。我们的假设是，内源性内皮CNP反向调节(周围)血管内皮细胞的病理性过度激活，从而减缓血管(动脉粥样硬化)和/或心脏炎症和重构(在缺血性或高血压性心脏病中)的发展。

The paracrine communication of endothelial cells (EC) with adjacent luminal, mural and extravascular cells is critically involved in cardiovascular homeostasis. EC dysfunction and altered crosstalk with in-flammatory and smooth muscle cells, fibroblasts and myocytes contributes to vascular and cardiac dis-eases such as atherosclerosis and hypertensive or ischemic heart remodeling. Among these paracrine factors, endothelium-derived C-type natriuretic peptide (CNP) complements the homeostatic actions of nitric oxide and prostacyclin. CNP moderates vascular resistance and thereby systemic blood pressure, and prevents microcirculatory inflammation, atherosclerosis and aneurysms. The cGMP-producing guanylyl cyclase B (GC-B) receptor for CNP is expressed in different vascular and adjacent cells. How-ever, the exact target cells and mechanisms mediating such protective CNP actions are unknown. Nota-bly, our ongoing in vitro/in vivo studies reveal CNP-induced GC-B/cGMP signaling in perivascular resident mast cells (MCs). Intravital microscopy studies of the mouse cremaster microcirculation demonstrate that exogenous, synthetic CNP fully prevents ischemia/reperfusion-induced MC degranulation and inflamma-tion. To study whether endogenous, endothelial CNP acts as paracrine modulator of perivascular MCs we generated a novel genetic mouse model with conditional, MC-restricted deletion of the GC-B receptor (MC GC-B KO mice). The present project will combine studies in MC deficient, MC reporter and MC GC-B KO mice with studies in cultured MCs. Our hypothesis is that endogenous, endothelial CNP counter-regulates the pathologic hyperactivation of (peri)vascular MCs and thereby moderates the development of vascular (atherosclerosis) and/or cardiac inflammation and remodeling (in ischemic or hypertensive heart disease).