Purinergic signaling, mediated mainly by G protein-coupled P2Y receptors (P2YRs), is now attracting attention as a new therapeutic target for preventing or treating cardiovascular diseases. Observations using mice with genetically modified P2YRs and/or treated with a pharmacological P2YR inhibitor have helped us understand the physiological and pathological significance of P2YRs in the cardiovascular system. P2YR-mediated biological functions are predominantly activated by mononucleotides released from non-adrenergic, non-cholinergic nerve endings or non-secretory tissues in response to physical stress or cell injury, though recent studies have suggested the occurrence of ligand-independent P2YR function through receptor-receptor interactions (oligomerization) in several biological processes. In this review, we introduce the functions of P2YRs and possible dimerization with G protein-coupled receptors (GPCRs) in the cardiovascular system. We focus especially on the crosstalk between uridine nucleotide-responsive P2Y₆R and angiotensin (Ang) II type1 receptor (AT1R) signaling, and introduce our recent finding that the P2Y₆R antagonist MRS2578 interrupts heterodimerization between P2Y₆R and AT1R, thereby reducing the risk of AT1R-stimulated hypertension in mice. These results strongly suggest that targeting P2Y₆R oligomerization could be an effective new strategy to reduce the risk of cardiovascular diseases.

嘌呤能信号主要由G蛋白偶联的P2Y受体（P2YRs）介导，作为预防或治疗心血管疾病的新治疗靶标，现在正受到关注。使用转基因P2YRs和/或用药理性P2YR抑制剂治疗的小鼠进行的观察有助于我们了解P2YRs在心血管系统中的生理和病理学意义。P2YR介导的生物学功能主要被非肾上腺素能，非胆碱能神经末梢或非分泌性组织释放的单核苷酸激活，以响应身体压力或细胞损伤，尽管最近的研究表明通过受体发生了配体独立的P2YR功能几个生物学过程中的β-受体相互作用（低聚）。在这篇评论中，我们介绍了P2YR的功能以及心血管系统中G蛋白偶联受体（GPCR）可能产生的二聚作用。我们特别关注尿苷核苷酸反应性P2Y之间的串扰₆ R和血管紧张素（Ang）II 1型受体（AT1R）信号，并介绍了我们最近的发现，即P2Y ₆ R拮抗剂MRS2578中断了P2Y ₆ R和AT1R之间的异源二聚化作用，从而降低了AT1R刺激的小鼠高血压的风险。这些结果强烈表明，针对P2Y ₆ R低聚可能是降低心血管疾病风险的有效新策略。