The P2Y6 Receptor as a Potential Keystone in Essential Hypertension.

IF 5.1 Q2 CELL BIOLOGY Function (Oxford, England) Pub Date : 2024-11-20 DOI:10.1093/function/zqae045
Nuria Daghbouche-Rubio, Inés Álvarez-Miguel, Victor Alejandro Flores, Jorge Rojo-Mencía, Manuel Navedo, Madeleine Nieves-Citrón, Pilar Cidad, M Teresa Pérez-García, José R López-López
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Abstract

Essential hypertension (HT) is a highly prevalent cardiovascular disease of unclear physiopathology. Pharmacological studies suggest that purinergic P2Y6 receptors (P2ry6) play important roles in cardiovascular function and may contribute to angiotensin II (AgtII) pathophysiological effects. Here, we tested the hypothesis that functional coupling between P2ry6 and AgtII receptors mediates altered vascular reactivity in HT. For this, a multipronged approach was implemented using mesenteric vascular smooth muscle cells (VSMCs) and arteries from Blood Pressure Normal (BPN) and Blood Pressure High (BPH) mice. Differential transcriptome profiling of mesenteric artery VSMCs identified P2ry6 purinergic receptor mRNA as one of the top upregulated transcripts in BPH. P2Y receptor activation elicited distinct vascular responses in mesenteric arteries from BPN and BPH mice. Accordingly, 10 µm UTP produced a contraction close to half-maximal activation in BPH arteries but no response in BPN vessels. AgtII-induced contraction was also higher in BPH mice despite having lower AgtII receptor type-1 (Agtr1) expression and was sensitive to P2ry6 modulators. Proximity ligation assay and super-resolution microscopy showed closer localization of Agtr1 and P2ry6 at/near the membrane of BPH mice. This proximal association was reduced in BPN mice, suggesting a functional role for Agtr1-P2ry6 complexes in the hypertensive phenotype. Intriguingly, BPN mice were resistant to AgtII-induced HT and showed reduced P2ry6 expression in VSMCs. Altogether, results suggest that increased functional coupling between P2ry6 and Agtr1 may contribute to enhanced vascular reactivity during HT. In this regard, blocking P2ry6 could be a potential pharmacological strategy to treat HT.

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P2Y6 受体是治疗原发性高血压的潜在基石。
本质性高血压(HT)是一种高发的心血管疾病,其生理病理尚不清楚。药理学研究表明,嘌呤能 P2Y6 受体(P2ry6)在心血管功能中发挥重要作用,并可能导致血管紧张素 II(AgtII)的病理生理效应。在这里,我们检验了 P2ry6 和 AgtII 受体之间的功能耦合介导 HT 血管反应性改变的假设。为此,我们使用肠系膜血管平滑肌细胞(VSMC)和来自 BPN(血压正常)和 BPH(血压高)小鼠的动脉采用了一种多管齐下的方法。肠系膜动脉 VSMC 的差异转录组图谱发现,P2ry6 嘌呤能受体 mRNA 是 BPH 中上调最多的转录本之一。P2Y 受体激活在 BPN 和 BPH 小鼠的肠系膜动脉中引起了不同的血管反应。因此,10 µM UTP 在 BPH 小鼠的肠系膜动脉中产生了接近半极限激活的收缩,但在 BPN 小鼠的血管中却没有反应。尽管BPH小鼠的AgtII受体1型(Agtr1)表达较低,但AgtII诱导的收缩也较高,并且对P2ry6调节剂敏感。近端连接试验(PLA)和超分辨率显微镜(SRM)显示,Agtr1 和 P2ry6 在 BPH 小鼠膜上/膜附近的定位更接近。在 BPN 小鼠中,这种近端结合减少,表明 Agtr1-P2ry6 复合物在高血压表型中的功能性作用。耐人寻味的是,BPN 小鼠对 AgtII 诱导的高血压有抵抗力,并且在 VSMC 中显示出 P2ry6 表达减少。总之,研究结果表明,P2ry6 和 Agtr1 之间功能性耦合的增加可能会导致高血压期间血管反应性的增强。因此,阻断 P2ry6 可能是治疗 HT 的一种潜在药物策略。
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CiteScore
5.70
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审稿时长
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