Andrew Hassall

Background: Coronary microvascular dysfunction (CMD) is increasingly recognized as a key contributor to ischemia with non-obstructive coronary arteries, contributing to various forms of heart failure, particularly in women and individuals with diabetes or metabolic syndrome. Reduced nitric oxide (NO) bioavailability is a central feature of CMD, compromising endothelial function and coronary perfusion. Recent studies highlight the P2Y₂ purinergic receptor (P2Y₂R) as a key upstream regulator of endothelial NO production, vascular tone, and angiogenesis, making it a promising therapeutic target in CMD.

Objective: This narrative review explores the mechanistic role of P2Y₂R in regulating endothelial function, vasodilation, and angiogenesis, and evaluates its therapeutic potential in CMD and related cardiovascular pathologies.

Methods: A comprehensive search of the PubMed database was conducted for articles published between 2017 and 2023 using MeSH terms and keywords such as “P2Y2 receptor,” “coronary microvascular dysfunction,” “endothelial nitric oxide synthase,” “angiogenesis,” “vascular tone,” and “endothelial signaling.”

Results: P2Y₂R expression is upregulated by aerobic exercise, enhancing coupling to endothelial nitric oxide synthase (eNOS) and improving vascular function.¹ Endothelial-specific deletion of P2Y₂R or its G proteins (Gαq/Gα11) reduces NO production and induces hypertension, highlighting its essential role in vascular health.^2,3,4 At the transcriptional level, P2Y₂R activation by extracellular nucleotides (e.g., UTP or ATP) triggers the PI3K/Akt/mTOR pathway, leading to phosphorylation of transcription factors c-Jun, c-Myc, and Foxo3a.⁵ These factors regulate genes critical for tissue remodeling, cell cycle progression, endothelial barrier function, and cell adhesion.⁵ Their activity facilitates endothelial cell responses to shear stress, promoting vascular remodeling and preventing hypertension. Knockdown studies demonstrate that the loss of these transcription factors impairs endothelial proliferation, migration, and tube formation, underscoring their crucial role in angiogenesis and microvascular repair.⁵ P2Y₂R also modulates the Hippo pathway and its downstream effectors, the transcriptional co-activators Yes-associated protein (YAP) in cardiovascular progenitor cells (CPCs). Overexpression of P2Y₂R downregulates Hippo kinases MST1 and LATS1, reducing phosphorylation of YAP and thereby activating YAP. Activated YAP enhances the proliferation and migration of CPCs, promoting myocardial repair and vascular regeneration, which is especially relevant in heart failure.⁶ P2Y₂R also exerts direct effects on vascular tone by activating TRPV4 channels to promote Ca²⁺ influx, facilitating eNOS phosphorylation and NO-dependent vasodilation.^7,8,9 P2Y₂R enhances endothelium-dependent hyperpolarization through KCa3.1 channels and connexin 37, enabling vasodilatory signals to propagate to surrounding vascular smooth muscle.^10,11 This dual mechanism reinforces dynamic control of coronary blood flow. P2Y₂R activation by extracellular ATP also stimulates the PLC-IP₃ pathway, triggering ER Ca²⁺ release and lysosomal Ca²⁺ flux via TRPML1^12,13,14. This Ca²⁺ cascade activates calcineurin, inducing TFEB nuclear translocation and transcription of lysosomal-autophagic genes.^12,13,14 In CMD, the P2Y₂-TFEB axis may enhance endothelial stress tolerance, autophagic clearance, and vascular repair, positioning it as a protective mechanism at the neurovascular and coronary interface.

Conclusion: P2Y₂R signaling is a key regulator of coronary microvascular function through NO production, transcription factor-mediated angiogenesis, progenitor cell activation, and vasodilatory pathways. Dysfunction of this signaling can contribute to CMD and hypertension. Therapeutic strategies targeting P2Y₂R, including pharmacologic agonists and exercise, may restore microvascular health and improve outcomes in CMD patients. Future research could focus on translating these findings to clinical therapies aimed at enhancing endothelial and microvascular repair.

Work Cited

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