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

内皮 C 型利钠肽局部、肥大细胞介导的心血管作用

• 批准号: 336002855
• 负责人: Professorin Dr. Michaela Kuhn
• 金额: --
• 依托单位: Physiologisches Institut
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2017
• 资助国家: 德国
• 起止时间: 2016-12-31 至 2021-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/336002855?language=en
• 关键词: Local; mast; cell; mediated; cardiovascular

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).

内皮细胞（EC）与邻近的腔，壁画和血管外细胞的旁分泌通信至关重要地参与心血管稳态。 EC功能障碍并随着刻张和平滑肌细胞，成纤维细胞和心肌细胞改变了串扰，从而有助于血管和心脏疾病，例如动脉粥样硬化以及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型纳地钠肽（CNP）补充了一氧化氮和前列环素的稳态作用。 CNP调节血管耐药性，从而防止微循环炎症，动脉粥样硬化和动脉瘤。 CNP的产生CGMP产生的Guanylyl环化酶B（GC-B）受体在不同的血管和相邻细胞中表达。但是，介导这种保护性CNP作用的确切目标细胞和机制尚不清楚。 nona-bly，我们正在进行的体外/体内研究表明，血管周期驻留肥大细胞（MCS）中CNP诱导的GC-B/CGMP信号传导。小鼠Cremaster显微循环的静脉显微镜研究表明，外源，合成的CNP完全阻止缺血/再灌注引起的MC脱粒和炎症。为了研究内源性内皮CNP是否充当血管周围MC的旁分泌调节剂，我们生成了一种新型的遗传小鼠模型，该模型具有GC-B受体（MC GC-B KO小鼠）的条件，MC限制性缺失。本项目将结合MC缺陷，MC Reporter和MC GC-B KO小鼠的研究与培养的MC的研究。我们的假设是内源性内皮CNP对（骨）血管MC的病理过度激活进行了反调节，从而缓解了血管（动脉粥样硬化）和/或心脏炎症和重塑（缺血性或高血压性心脏病）的发育（动脉粥样硬化）。