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

• Applicant: Professorin Dr. Michaela Kuhn
• Subject Area: Anatomy and Physiology
• Term: from 2017 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 336002855

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).

• DFG Programme: Research Grants