Role of the Purinergic P2Y2 Receptor in Pulmonary Hypertension

Abstract

Pulmonary arterial hypertension (PAH), group 1 pulmonary hypertension (PH), is a fatal disease that is characterized by vasoconstriction, increased pressure in the pulmonary arteries, and right heart failure. PAH can be described by abnormal vascular remodeling, hyperproliferation in the vasculature, endothelial cell dysfunction, and vascular tone dysregulation. The disease pathomechanisms, however, are as yet not fully understood at the molecular level. Purinergic receptors P2Y within the G-protein-coupled receptor family play a major role in fluid shear stress transduction, proliferation, migration, and vascular tone regulation in systemic circulation, but less is known about their contribution in PAH. Hence, studies that focus on purinergic signaling are of great importance for the identification of new therapeutic targets in PAH. Interestingly, the role of P2Y2 receptors has not yet been sufficiently studied in PAH, whereas the relevance of other P2Ys as drug targets for PAH was shown using specific agonists or antagonists. In this review, we will shed light on P2Y receptors and focus more on the P2Y2 receptor as a potential novel player in PAH and as a new therapeutic target for disease management.

Keywords: pharmacological approach; pulmonary arterial hypertension; purinergic P2Y2 receptor.

Figure 1

Purinergic receptor tree, and the classification of P2Y2: Adenosine receptors and ATP receptors (P1 and P2, respectively).

Figure 2

P2Y2 mediated signaling pathways that are generally expected in different cell types and tissues, including the pulmonary vasculature. Abbreviations: MRS = MRS2768; DAG = diacylglycerol; PKC = proteinkinase C; Erk1/2 = extracellular-signal regulated kinases; PLCβ = phospholipase C (β); IP3 = inositol trisphosphate; CaM = calmodulin; CaMK = Ca²⁺/calmodulin-dependent protein kinase; CREB = cAMP response element-binding protein; NOS = nitric oxide (NO) synthase; SH3 = SRC homology 3 domain; Gα, Gβ, and Gγ = G-protein subunits (α, β and γ); Src = proto-oncogene tyrosine-protein kinase; PECAM-1 = platelet endothelial cell adhesion molecule; Pyk2 = protein tyrosine kinase 2 beta; VEGFR-2 = vascular endothelial growth factor receptor 2; VE-cadherin = vascular endothelial cadherin; Rac1 = Ras-related C3 botulinum toxin substrate 1; PI3K = phosphoinositide 3-kinases; Akt = protein kinase B (PKB) [3,25,91,92,93,94,95,96,97,98,99,100,101].

Figure 3

Endothelial P2Y2 interactions with Pannexin1 and Piezo1 under fluid shear stress conditions in systemic circulation. Fluid shear stress activates Piezo1, a mechanosensitive channel that mediates ATP release via pannexin1 channels. Ectonucleotidases hydrolyze the extracellular nucleotide ATP to ADP, AMP, and adenosine, which activate P2Y2 and other P2Y receptors, suggesting P2Y2 as being downstream of Piezo1 [99,145,151,152,153,154].