Universität zu Köln

Chen, Wen, Werner, Franziska, Illerhaus, Anja, Knopp, Tanja, Voelker, Katharina, Potapenko, Tamara, Hofmann, Ulrich, Frantz, Stefan, Baba, Hideo A., Roesch, Melanie, Zernecke, Alma, Karbach, Susanne, Wenzel, Philip and Kuhn, Michaela (2020). Stabilization of Perivascular Mast Cells by Endothelial CNP (C-Type Natriuretic Peptide). Arterioscler. Thromb. Vasc. Biol., 40 (3). S. 682 - 697. PHILADELPHIA: LIPPINCOTT WILLIAMS & WILKINS. ISSN 1524-4636

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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-Cre(TG) 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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Chen, Wen UNSPECIFIED UNSPECIFIED UNSPECIFIED Werner, Franziska UNSPECIFIED UNSPECIFIED UNSPECIFIED Illerhaus, Anja UNSPECIFIED UNSPECIFIED UNSPECIFIED Knopp, Tanja UNSPECIFIED UNSPECIFIED UNSPECIFIED Voelker, Katharina UNSPECIFIED UNSPECIFIED UNSPECIFIED Potapenko, Tamara UNSPECIFIED UNSPECIFIED UNSPECIFIED Hofmann, Ulrich UNSPECIFIED UNSPECIFIED UNSPECIFIED Frantz, Stefan UNSPECIFIED UNSPECIFIED UNSPECIFIED Baba, Hideo A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Roesch, Melanie UNSPECIFIED UNSPECIFIED UNSPECIFIED Zernecke, Alma UNSPECIFIED UNSPECIFIED UNSPECIFIED Karbach, Susanne UNSPECIFIED UNSPECIFIED UNSPECIFIED Wenzel, Philip UNSPECIFIED UNSPECIFIED UNSPECIFIED Kuhn, Michaela UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-342216
DOI:	10.1161/ATVBAHA.119.313702
Journal or Publication Title:	Arterioscler. Thromb. Vasc. Biol.
Volume:	40
Number:	3
Page Range:	S. 682 - 697
Date:	2020
Publisher:	LIPPINCOTT WILLIAMS & WILKINS
Place of Publication:	PHILADELPHIA
ISSN:	1524-4636
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language DEEP-VEIN THROMBOSIS; NITRIC-OXIDE; INHIBITION; ACTIVATION; HEART Multiple languages Hematology; Peripheral Vascular Disease Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/34221