肺动脉高压（PAH）血管重构涉及内皮间质转化、平滑肌细胞表型转化和细胞外基质增生等病理过程。本项目预实验首次发现：低氧性PAH大鼠肺血管内皮小脑肽-2（CBLN2）表达显著上调；低氧条件下肺血管内皮细胞合成分泌CBLN2增加，促进了内皮间质转化和平滑肌细胞表型转化，沉默CBLN2表达可取消上述作用。因此，申请人率先提出以下观点：低氧条件下CBLN2可能通过促进肺血管内皮间质转化和平滑肌细胞表型转化参与PAH的发生发展。本项目拟从动物、细胞和分子水平重点探讨以下内容: ①建立低氧性PAH大鼠模型，明确CBLN2促肺血管内皮间质转化和平滑肌细胞表型转化作用；②利用低氧培养的肺动脉内皮细胞，阐明CBLN2促内皮间质转化作用机制；③利用内皮细胞和平滑肌细胞低氧共培养模型，阐明CBLN2促平滑肌细胞表型转化作用机制。本项目将有助于阐明PAH血管重构机制，为寻找防治PAH的新靶点和新药提供理论依据。

Pulmonary arterial hypertension (PAH) vascular remodeling involves the pathological processes of endothelial-mesenchymal transition, vascular smooth muscle cell phenotypic modulation, and the increase of extracellular matrix production. Our pilot study found that the expression of cerebellin-2 (CBLN2) was up-regulated in intima of pulmonary vascular in hypoxia-induced PAH rats; the synthesis and secretion of CBLN2 in pulmonary vascular endothelial cells were significantly increased under hypoxia, which promotes the occurrence of pulmonary vascular endothelial-mesenchymal transition and smooth muscle cell phenotypic modulation, and these phenomena were reversed by CBLN2 siRNA. Therefore, we raise the point of view for the first time as follow: CBLN2 may contribute to the development of hypoxia-induced PAH vascular remodeling by promoting pulmonary vascular endothelial-mesenchymal transition and smooth muscle cell phenotypic modulation. We will explore the following contents at animal, cellular and molecular levels: (1) By using a rat model of hypoxia-induced PAH, we will verify the important/potential role of CBLN2 in promotion of endothelial-mesenchymal transition and vascular smooth muscle cell phenotypic modulation; (2) By using a model of hypoxia-induced pulmonary arterial endothelial cells (PAECs), we will clarify the underlying mechanisms for CBLN2 in promoting endothelial-mesenchymal transition. (3) By using a co-culture model of PAECs and pulmonary arterial smooth muscle cells (PASMCs) under hypoxia, we will clarify the underlying mechanisms for CBLN2 in promoting vascular smooth muscle cell phenotypic modulation. This study will contribute to the understanding of the pathogenesis of PAH vascular remodeling, and provide theoretical basis for seeking new targets for drug research and development.