Stabilization of Perivascular Mast Cells by Endothelial CNP (C-Type Natriuretic Peptide)

Chen W, Werner F, Illerhaus A, Knopp T, Voelker K, Potapenko T, Hofmann U, Frantz S, Baba HA, Roesch M, Zernecke A, Karbach S, Wenzel P, Kuhn M (2020)

Publication Type: Journal article

Publication year: 2020

Journal

Arteriosclerosis, Thrombosis, and Vascular Biology American Heart Association

Book Volume: 40

Pages Range: 682-696

Journal Issue: 3

DOI: 10.1161/ATVBAHA.119.313702

Abstract

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.

Involved external institutions

Julius-Maximilians-Universität Würzburg DE Germany (DE) Universität zu Köln DE Germany (DE) Universitätsklinikum Würzburg DE Germany (DE) Johannes Gutenberg-Universität Mainz (JGU) DE Germany (DE) Universität Duisburg-Essen (UDE) DE Germany (DE)

How to cite

APA:

Chen, W., Werner, F., Illerhaus, A., Knopp, T., Voelker, K., Potapenko, T.,... Kuhn, M. (2020). Stabilization of Perivascular Mast Cells by Endothelial CNP (C-Type Natriuretic Peptide). Arteriosclerosis, Thrombosis, and Vascular Biology, 40(3), 682-696. https://doi.org/10.1161/ATVBAHA.119.313702

MLA:

Chen, Wen, et al. "Stabilization of Perivascular Mast Cells by Endothelial CNP (C-Type Natriuretic Peptide)." Arteriosclerosis, Thrombosis, and Vascular Biology 40.3 (2020): 682-696.

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