OBJECTIVE Activated perivascular mast cells (MCs) participate in different cardiovascular diseases. Many factors provoking MC degranulation have been described, while physiological counterregulators are barely known. Endothelial CNP (C-type natriuretic peptide) participates in the maintenance of vascular barrier integrity, but the target cells and mechanisms are unclear. Here, we studied whether MCs are regulated by CNP. Approach and Results: In cultured human and murine MCs, CNP activated its specific GC (guanylyl cyclase)-B receptor and cyclic GMP signaling. This enhanced cyclic GMP-dependent phosphorylation of the cytoskeleton-associated VASP (vasodilator-stimulated phosphoprotein) and inhibited ATP-evoked degranulation. To elucidate the relevance in vivo, mice with a floxed GC-B (Npr2) gene were interbred with a Mcpt5-CreTG line to generate mice lacking GC-B in connective tissue MCs (MC GC-B knockout). In anesthetized mice, acute ischemia-reperfusion of the cremaster muscle microcirculation provoked extensive MC degranulation and macromolecule extravasation. Superfusion of CNP markedly prevented MC activation and endothelial barrier disruption in control but not in MC GC-B knockout mice. Notably, already under resting conditions, such knockout mice had increased numbers of degranulated MCs in different tissues, together with elevated plasma chymase levels. After transient coronary occlusion, their myocardial areas at risk and with infarction were enlarged. Moreover, MC GC-B knockout mice showed augmented perivascular neutrophil infiltration and deep vein thrombosis in a model of inferior vena cava ligation. CONCLUSIONS CNP, via GC-B/cyclic GMP signaling, stabilizes resident perivascular MCs at baseline and prevents their excessive activation under pathological conditions. Thereby CNP contributes to the maintenance of vascular integrity in physiology and disease.

中文翻译：

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内皮CNP（C型利钠肽）稳定血管周围肥大细胞。

目的活化的血管周围肥大细胞（MCs）参与不同的心血管疾病。已经描述了许多引起MC脱粒的因素，而生理反调节剂却鲜为人知。内皮CNP（C型利钠肽）参与维持血管屏障的完整性，但靶细胞和机制尚不清楚。在这里，我们研究了MC是否受CNP调节。方法和结果：在培养的人和鼠MC中，CNP激活了其特异性的GC（鸟苷酸环化酶）-B受体和循环GMP信号。这种增强的细胞骨架相关的VASP（血管扩张剂刺激的磷蛋白）的循环GMP依赖性磷酸化作用，并抑制了ATP引起的脱粒。为了阐明体内相关性，将具有荧光GC-B（Npr2）基因的小鼠与Mcpt5-CreTG系杂交，以生成结缔组织MC中缺少GC-B的小鼠（MC GC-B敲除）。在麻醉的小鼠中，提睾肌微循环的急性缺血-再灌注引起广泛的MC脱粒和大分子外渗。CNP的灌注显着阻止了对照组中MC的激活和内皮屏障的破坏，但在MC GC-B基因敲除小鼠中却没有。值得注意的是，这种敲除小鼠已经处于静止状态，在不同组织中脱颗粒的MC数量增加，血浆糜酶水平升高。短暂性冠状动脉闭塞后，他们处于危险和梗死状态的心肌面积增大。此外，MC GC-B基因敲除小鼠在下腔静脉结扎模型中显示血管周围中性粒细胞浸润增加和深静脉血栓形成。结论CNP通过GC-B /循环GMP信号传导将基线时的血管周围MC稳定化，并防止其在病理情况下过度活化。因此，CNP有助于维持生理和疾病中的血管完整性。