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Theranostics 2022; 12(11):5172-5188. doi:10.7150/thno.71585 This issue Cite

Research Paper

Endothelial S1pr2 regulates post-ischemic angiogenesis via AKT/eNOS signaling pathway

Caixia Zhou^1†, Yashu Kuang^1†, Qinyu Li^2†, Yunhao Duan¹, Xiuxiang Liu¹, Jinnan Yue¹, Xiaoli Chen¹, Jie Liu¹, Yuzhen Zhang^1✉, Lin Zhang^1✉

1. Key Laboratory of Arrhythmias of the Ministry of Education of China, Research Center for Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China.
2. Postgraduate training base in Shanghai Gongli Hospital, Ningxia Medical University, Ningxia, 750004, China.
†These authors contributed equally to this work

✉ Corresponding authors: Lin Zhang, MD, PhD. Key Laboratory of Arrhythmias of the Ministry of Education of China. Research Center for Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine, 150 Jimo Rd, Pudong New District, Shanghai, 200120, China. Tel:86-21-61569673, e-mail: zhanglin1209edu.cn. Yuzhen Zhang, MD, PhD. Key Laboratory of Arrhythmias of the Ministry of Education of China. Research Center for Translational Medicine Shanghai East Hospital, Tongji University School of Medicine, 150 Jimo Rd, Pudong New District, Shanghai, 200120, China.Tel:86-21-61569673, e-mail: yzzhang-tjedu.cn More

Abstract

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.

Keywords: Sphingosine 1-phosphate receptor 2, Endothelial cells, Hindlimb ischemia, Angiogenesis

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