Role of P2Y6 receptor in pulmonary arterial hypertension and vascular remodeling following cigarette smoke exposure in mice

Chronic Obstructive Pulmonary Disease (COPD) is a leading cause of death, associated with remodeling and pulmonary arterial hypertension (PAH), and characterized by increased vascular tone and vascular structural alterations. Purinergic receptor P2Y6 is expressed in the vascular wall and has been implicated in fibrotic and contractile responses; however, its role in COPD-associated PAH remains poorly understood. To determine the association of P2Y6 receptor expression with PAH and vascular remodeling, following cigarette smoke (CS) exposure in mice. After Ethics Committee approval, 60 female A/J mice were exposed to CS for six months and treated with the P2Y6 antagonist, MRS2578, for three months. PAH and cardiac remodeling were assessed by echocardiography, Fulton index (FI), right ventricular (RV) morphometry, fibrosis, and gene expression. Lungs were analyzed by histology, and P2Y6, α-smooth muscle actin (α-SMA), and collagen immunofluorescence. Emphysema and pulmonary arterial remodeling were evaluated by histology. Precision-cut lung slices (PCLS) from 48 female A/J mice were exposed to CS extract (CSE) to determine vasoreactivity. Parametric or non-parametric tests were used. CS exposure induced emphysema and echocardiographic features of PAH, including reduced pulmonary artery acceleration time (PAAT), and RV hypertrophy. Perivascular α-SMA and P2Y6 expression were increased and co-expressed despite unchanged arterial wall thickness. MRS2578 prevented PAH-related changes, reduced perivascular α-SMA-positive cells, and inhibited vasoconstrictor responses in CSE-exposed lung slices. This study suggests a role of P2Y6 in PAH and vascular remodeling in CS in vivo exposure, as well as a functional role in the acute vasoconstriction after CSE ex vivo exposure. • Cigarette smoke induces pulmonary hypertension and vascular remodeling in mice. • P2Y6 expression increases in perivascular cells and co-localizes with α-SMA. • P2Y6 antagonism prevents right ventricular hypertrophy and PAH features. • Cigarette smoke enhances pulmonary vasoconstriction ex vivo via P2Y6. • Targeting P2Y6 reduces remodeling and acute vasoconstrictor responses.