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.
Highlights
Pulmonary hypertension (PH) represents a heterogeneous group of clinical entities, defined as a mean pulmonary artery pressure above 20 mmHg [1]
Recent studies have demonstrated a purinergic receptor P2Y2 involvement in nitric oxide (NO) secretion, which results in systemic vasodilation, and suggested the P2Y2 receptor transmitted the fluid shear stress (FSS) signaling in order to keep NO secretion at physiological levels [25]
Activation of Go through P2Y2 is reported to mediate the activation of RhoA [91,108], whereas activation of Gα12 through P2Y2 is shown to activate Rac, RacGEF, and Vav2, which play a significant role in cell migration [91,110]
Summary
Pulmonary hypertension (PH) represents a heterogeneous group of clinical entities, defined as a mean pulmonary artery pressure above 20 mmHg [1]. The P2Y2 receptor is known to be associated with other diseases, such as dry eye syndrome [29,30], accommodative spasm [31], and cystic fibrosis [32,33] This has stimulated many researchers to pharmacologically target P2Y2 to develop new treatment approaches for these diseases. This pulmonary vascular inflammation in PAH has been shown to contribute to progressive pulmonary vascular remodeling [59] In this regard, it is interesting to note that P2Y2 receptor expression was revealed in the cells of the innate immune system, such as microphages and neutrophils. P2Y2 activation on alveolar macrophages results in an increase of intracellular Ca2+ , which facilitates phagocytosis [40]
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