Pericyte-mediated effects of natriuretic peptides: role in the regulation of lung microvascular resistance and the development of pulmonary hypertension

• Applicants: Dr. Swati Dabral, Ph.D.; Professorin Dr. Michaela Kuhn
• Subject Area: Anatomy and Physiology
• Term: since 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 449137812

Pulmonary hypertension (PH) is a frequent complication of many chronic lung diseases. The pathophysiology is multifactorial and includes chronic or recurrent hypoxia and augmented (peri)vascular expression of growth factors and inflammatory mediators. This provokes remodelling of small arterioles and muscularization of very distal, normally non-muscularized vessels. Recent studies of human samples indicated that loss and detachment of microcirculatory pericytes as well as their migration, ectopic proliferation and differentiation contribute to microvessel loss, remodelling and inflammation in PH. While many stressors contributing to pathological pulmonary microvascular remodelling were described, physiological counterregulators are barely known. Our experimental studies in vitro/in vivo revealed that the cardiac hormone atrial natriuretic peptide (ANP), via its guanylyl cyclase A (GC-A) receptor and cyclic GMP production, regulates pericyte functions. Such endocrine actions are locally complemented by endothelial C-type natriuretic peptide (CNP), activating cGMP signalling via its GC-B receptor. Notably, in the retinal microcirculation ANP attenuates hypoxia- or TGF-beta-triggered pericyte apoptosis, microvessel loss and inflammation and thereby experimentally-induced proliferative retinopathy. In the systemic microcirculation ANP and CNP counter-regulate endothelin-1-induced pericyte contractions, moderating peripheral resistance and arterial blood pressure. We observe that the GC-A and GC-B receptors are also expressed in lung pericytes, with unknown functions. Here we propose comparative molecular and functional studies in mice with conditional, pericyte-restricted inactivation of either receptor and respective control mice. We aim to dissect the role(s) of ANP- vs CNP-driven pericyte cGMP signalling pathways in the regulation of pulmonary distal arteriolar and capillary tone and recruitment as well as in pathological lung microvascular remodelling, inflammation and PH. These in vivo/ex vivo studies will be complemented with mechanistic studies of GC-A/GC-B function and dysfunction in cultured human (and murine) pericytes from control vs PH patients (and mice), to foster our understanding of the cause and pathogenesis of PH, i.e. the potential protective role and therapeutical relevance of natriuretic peptide/cyclic GMP signalling in pericytes.

• DFG Programme: Research Grants