CNP/cGMP signalling inhibits metabolic remodelling of lung pericytes from patients with pulmonary hypertension

Metabolic reprogramming is a fundamental hallmark of cells under various pathological conditions. In pulmonary hypertension (PH), the severe vascular remodeling is linked to metabolic dysregulation of endothelial and smooth muscle cells. The contribution of pericytes, essential components of the microvascular unit, to the pathogenesis of PH remains largely unexplored. We studied the functional and metabolic alterations of lung pericytes from PH patients and the effect of C-type natriuretic peptide (CNP) and GC-B/cGMP signaling.In comparison to control pericytes (obtained from "healthy" human lungs), cultured PH pericytes exhibited heightened proliferation, glucose uptake and glycolysis (extracellular acidification rate) in response to platelet derived growth factor-BB (PDGF-BB). CNP, via cGMP signaling, attenuated PDGF-BB-induced proliferation and glucose uptake of PH and control pericytes. Intriguingly, CNP reduced PDGF-BB induced glycolysis exclusively in PH cells, indicating differential regulation of glycolytic pyruvate utilization. Our metabolomics analyses identified a novel and distinct metabolic pathway enhancing de novo pyrimidine synthesis in PH pericytes. Notably, in vitro, this pathway was strongly counter-regulated by CNP. Supporting the pathomechanistic relevance of these findings, immunohistochemistry showed strong upregulation of the involved metabolic machinery in lungs from PH patients, while CNP mRNA expression was markedly downregulated.Our studies reveal that pericytes from PH patients exhibit a distinct metabolic signaling pathway contributing to their hyperproliferation. Loss of the inhibitory effects of endogenous CNP may contribute to lung microvascular remodeling in such patients. Hence, administering exogenous stabilized CNP to patients with PH could attenuate disease progression by averting pathological proliferation and metabolic alterations of lung pericytes. Minhee Noh and Ankita Mitra contributed equally as first authors.VinicioA. de Jesus Perez, Michaela Kuhn and Swati Dabral contributed equally as last authors.