The physiological function of the purinergic receptor P2Y2 in pulmonary arterial endothelial cells and its role in pulmonary hypertension

Objective: Pulmonary arterial hypertension (PAH) is a result of pathological processes that involve the G protein-coupled receptors (GPCRs). Crucial mediators of vasodilation, e.g. nitric oxide (NO) or prostacyclin are released from endothelial cells to control the vascular tone. Hence, endothelial dysfunction is defined as a decreased secretion of vasodilators that contributes with other factors to the onset of vasoconstriction. Recent studies have demonstrated the participation of the purinergic receptor P2Y2, a GPCR in NO secretion. The aim of our investigations is to examine the function of P2Y2 in human pulmonary arterial endothelial cells (HPAECs) as well as a possible involvement in the molecular pathogenesis of PAH.

Results: The treatment of HPAECs with MRS2768 (a selective agonist of P2Y2) was associated with increased concentrations of the inositol 1,4,5-triphosphate (IP3), indicating a signaling event via Gα_q/11. Furthermore, the treatment with MRS2768 led to activation of p-Akt and p-eNOS in time- and concentration-dependent manners and increased the secretion of NO by HPAECs. HPAECs cultured under hypoxic conditions (1%O₂) showed altered regulation of P2Y2 on mRNA levels compared to the normoxic controls (21% O₂). Immunohistochemistry-staining showed an increased expression of P2Y2 in pulmonary arteries from PAH-lung specimens.

Conclusion: In this study, we demonstrate the capability of the P2Y2 agonist MRS2768 to increase the endothelial NO secretion in vitro. These findings indicate a vasodilatory role of P2Y2 in pulmonary arteries and identify P2Y2 as a potential target in pharmacological treatment of PAH. The significance of P2Y2 in PAH lungs and hemodynamic relevance must further be examined in HPAEC from PAH patients as well as in vivo experiments.