巨噬细胞源性sVEGFR-1通过调控肺动脉内皮细胞mTOR自噬通路参与肺动脉高压内皮损伤的机制研究

内皮细胞损伤和巨噬细胞聚集是肺动脉高压（PAH）领域关注的热点。前期研究证实，PAH患者肺组织中mTOR水平下降，其过表达可缓解PAH小鼠症状，并通过抑制细胞自噬降低低氧诱导的肺动脉内皮细胞（PAEC）增殖。PAH小鼠分离的巨噬细胞可高表达sVEGFR-1，并诱导PAEC凋亡。sVEGFR-1的配体VEGF被证实与mTOR共同作用参与多种疾病发生。因此，我们提出“巨噬细胞源性sVEGFR-1通过与mTOR作用调控内皮细胞自噬，进而影响内皮损伤，参与PAH发展进程”的假说。本研究拟构建sVEGFR-1过表达和缺失的巨噬细胞模型，分析其对内皮细胞增殖及凋亡的作用；构建低氧诱发的PAH小鼠模型，探讨sVEGFR-1对PAH小鼠的影响；分析mTOR介导的自噬通路在其中的作用，明确sVEGFR-1是否与mTOR共同作用，影响内皮损伤及自噬进程，参与PAH的发展，从而为PAH预防和治疗提供新靶点。

Endothelial cell injury and macrophage accumulation have attracted increasing attention in pulmonary arterial hypertension (PAH). In our previous study, the low expression of mammalian target of rapamycin (mTOR) had been observed in lung tissues from patients with PAH. Overexpression of mTOR obviously alleviated PAH symptoms in mice, and attenuated chronic hypoxia-induced pulmonary artery endothelial cell (PAECs) proliferation by suppressing cell autophagy pathway. A high secretion of soluble vascular endothelial growth factor receptor 1 (sVEGFR-1) was demonstrated in macrophages isolated from PAH mice. These macrophages could induce the apoptosis PAECs. A ligand of sVEGFR-1, VEGF, have been manifested to be involved in many diseases by interacting with mTOR. Therefore, we speculate that macrophage-derived sVEGFR-1 can regulate endothelial cell injury and the development of PAH by mTOR-mediated autophagy pathway in PAEC. In this study, we will establish the sVEGFR-1-overexpressed and -silenced macrophages, and investigate the effect of sVEGFR-1 on PAEC proliferation and apoptosis. The chronic hypoxia-induced PAH mice models will be constructed to explore the function of sVEGFR-1 on the pathological progression of PAH in vivo. Additionally, the effect of mTOR-mediated autophagy in PAEC will be also investigated during this process. We will clarify whether sVEGFR-1 affects PAEC injury and autophage by cross-talking with mTOR in the process of PAH. Together, this research will provide a promising target for PAH prevention and treatment.