GPR4 signaling is essential for the promotion of acid-mediated angiogenic capacity of endothelial progenitor cells by activating STAT3/VEGFA pathway in patients with coronary artery disease.
GPR4 signaling is essential for the promotion of acid-mediated angiogenic capacity of endothelial progenitor cells by activating STAT3/VEGFA pathway in patients with coronary artery disease.
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DOI：
10.1186/s13287-021-02221-z
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发表时间：
2021-02-25
影响因子：
7.5
通讯作者：
Lin X
中科院分区：
文献类型：
--
作者：
Ouyang S;Li Y;Wu X;Wang Y;Liu F;Zhang J;Qiu Y;Zhou Z;Wang Z;Xia W;Lin X
冠状动脉疾病（CAD）患者的特征是血管再生能力下降，这与内皮祖细胞（EPCs）功能障碍有关。G蛋白偶联受体4（GPR 4）是一种质子敏感的G蛋白偶联受体（GPCR），在酸性微环境中促进新生血管形成。然而，GPR 4在调节CAD患者EPCs响应缺血组织中产生的酸性的血管生成能力中的作用仍然完全不清楚。在不同pH环境中评价从CAD患者和健康受试者收集的EPCs的血管生成能力。在体外和体内分析GPR 4调节EPC介导的血管生成的功能。通过基因过表达和抑制进一步研究了下游机制。酸性环境预刺激显著增强了非CAD组EPCs在体内和体外的血管生成能力，而相同的治疗在CAD组中产生相反的结果。在四种典型的质子敏感GPCR中，GPR 4在EPCs中的表达最高。GRP 4的表达在CAD患者的EPCs中显著低于非CAD个体的EPCs，与酸刺激无关。siRNA介导的GPR 4的敲低以及随后STAT 3磷酸化的降低模拟了来自CAD患者的EPCs在pH 6.4下而不是在pH 7.4下的受损功能。在酸性环境中，GPR 4表达的升高通过激活STAT 3/VEGFA信号通路恢复了CAD患者EPCs介导的新血管形成。此外，通过阻断STAT 3/VEGFA信号通路，GPR 4上调对EPC介导的血管生成能力的有益影响被消除。我们目前的研究首次证明GPR 4的缺失是导致CAD患者EPCs质子敏感和血管生成能力下降的原因。GPR 4表达的增强通过激活STAT 3/VEGF信号传导促进EPCs的新血管形成。这一发现暗示GPR 4是以缺血组织中受损的新血管形成为特征的CAD的潜在治疗靶点。在线版本包含补充材料，可通过10.1186/s13287-021-02221-z获得。
Patients with coronary artery disease (CAD) are characterized by a decline in vascular regeneration, which is related to the dysfunction of endothelial progenitor cells (EPCs). G-protein-coupled receptor 4 (GPR4) is a proton-sensing G-protein-coupled receptor (GPCR) that contributes to neovascularization in acidic microenvironments. However, the role of GPR4 in regulating the angiogenic capacity of EPCs from CAD patients in response to acidity generated in ischemic tissue remains completely unclear. The angiogenic capacity of EPCs collected from CAD patients and healthy subjects was evaluated in different pH environments. The GPR4 function of regulating EPC-mediated angiogenesis was analyzed both in vitro and in vivo. The downstream mechanisms were further investigated by genetic overexpression and inhibition. Acidic environment prestimulation significantly enhanced the angiogenic capacity of EPCs from the non-CAD group both in vivo and in vitro, while the same treatment yielded the opposite result in the CAD group. Among the four canonical proton-sensing GPCRs, GPR4 displays the highest expression in EPCs. The expression of GRP4 was markedly lower in EPCs from CAD patients than in EPCs from non-CAD individuals independent of acid stimulation. The siRNA-mediated knockdown of GPR4 with subsequent decreased phosphorylation of STAT3 mimicked the impaired function of EPCs from CAD patients at pH 6.4 but not at pH 7.4. Elevating GPR4 expression restored the neovessel formation mediated by EPCs from CAD patients in an acidic environment by activating STAT3/VEGFA signaling. Moreover, the beneficial impact of GPR4 upregulation on EPC-mediated angiogenic capacity was abrogated by blockade of the STAT3/VEGFA signaling pathway. Our present study demonstrated for the first time that loss of GPR4 is responsible for the decline in proton sensing and angiogenic capacity of EPCs from CAD patients. Augmentation of GPR4 expression promotes the neovessel formation of EPCs by activating STAT3/VEGF signaling. This finding implicates GPR4 as a potential therapeutic target for CAD characterized by impaired neovascularization in ischemic tissues. The online version contains supplementary material available at 10.1186/s13287-021-02221-z.