Endothelial S1pr2 regulates post-ischemic angiogenesis via AKT/eNOS signaling pathway.
Endothelial S1pr2 regulates post-ischemic angiogenesis via AKT/eNOS signaling pathway.
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DOI：
10.7150/thno.71585
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发表时间：
2022
期刊：
影响因子：
12.4
通讯作者：
Zhang, Lin
中科院分区：
文献类型：
--
作者：
Zhou, Caixia;Kuang, Yashu;Li, Qinyu;Duan, Yunhao;Liu, Xiuxiang;Yue, Jinnan;Chen, Xiaoli;Liu, Jie;Zhang, Yuzhen;Zhang, Lin
目的：了解缺血后血管生成的调控机制，探索新的治疗靶点，有效改善外周动脉疾病(PAD)患者的血运重建。缺血后血管生成是一个高度协调的过程，涉及血管内皮细胞(ECs)的增殖、迁移和组装成毛细血管。我们发现后肢缺血(HLI)后内皮细胞S1PR2(鞘氨醇1-磷酸受体2)的表达显著减少。因此，我们推测EC-S1PR2可能参与了外周动脉疾病(PAD)缺血后血管生成和血流恢复的调节。方法和结果：我们建立了EC特异性的S1PR2功能丧失和S1PR2功能获得的小鼠。我们的研究表明，EC特异性的S1PR2功能丧失显著促进了缺血后的血管生成，促进了股动脉结扎后的血流恢复，而EC特异性的S1PR2功能恢复严重阻碍了缺血后的血管生成，降低了缺血肢体的血流恢复。接下来我们发现S1PR2抑制了AKT/eNOS信号通路，从而抑制了EC的增殖/迁移和血管生成活性。正如预期的那样，JTE013对S1PR2的药理抑制改善了缺血后的血管生成，并改善了股动脉结扎后的血流灌流。此外，我们还开发了包装S1PR2-siRNA的RGD-多肽磁性纳米颗粒，该纳米颗粒可以特异性地靶向内皮细胞，并在体内实现了对S1PR2表达的有效沉默。这一抑制S1PR2的EC靶向策略显著增强了缺血后血管生成，并增加了HLI后的血液灌注量，为外周动脉疾病患者提供了一个新的治疗靶点。结论：本研究表明，表达血管内皮细胞的S1PR2严格控制缺血后血管生成和血流灌流恢复。本研究为EC靶向敲除S1PR2基因作为治疗外周动脉疾病的新的干预措施提供了新的策略。
Aims: It is important to understand the mechanism that regulates post-ischemic angiogenesis and to explore a new therapeutic target for an effective improvement of revascularization in peripheral artery disease (PAD) patients. Post-ischemic angiogenesis is a highly orchestrated process, which involves vascular endothelial cells (ECs) proliferation, migration and assembly into capillaries. We found a significant reduction of S1pr2 (sphingosine 1-phosphate receptor 2) in endothelial cells after hindlimb ischemia (HLI). We thus hypothesized that EC-S1pr2 might be involved in the regulation of post-ischemic angiogenesis and blood flow recovery during peripheral arterial disease (PAD). Methods and Results: We generated both EC-specific S1pr2 loss-of-function and S1pr2 gain-of-function mice. Our study showed that EC-specific S1pr2 loss-of-function significantly enhanced post-ischemic angiogenesis and improved blood flow recovery upon femoral artery ligation, whereas the EC-specific S1pr2 gain-of-function severely hindered post-ischemic angiogenesis and reduced blood flow recovery in ischemic limbs. We next identified that S1pr2 inhibited AKT/eNOS signaling pathway, and thus inhibited EC proliferation/migration and angiogenic activity. As expected, pharmacological inhibition of S1pr2 by JTE013 improved post-ischemic angiogenesis and improved blood flow perfusion after femoral artery ligation. Moreover, we developed RGD-peptide magnetic nanoparticles packaging S1pr2-siRNA which specifically targeted ECs and achieved an efficient silencing of S1pr2 expression in ECs in vivo. This EC-targeted strategy to dampen S1pr2 significantly enhanced post-ischemic angiogenesis and boosted blood perfusion after HLI, supplying a novel therapy target for patients with peripheral arterial disease. Conclusions: This present study demonstrates that EC-expressing S1pr2 tightly controls post-ischemic angiogenesis and blood flow perfusion recovery. This research provides a novel strategy for EC-target knockdown of S1pr2 as a new therapeutic intervention for patients with peripheral artery disease.
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