HGF介导的Notch/Dll4信号通路在息肉状脉络膜血管病变中的作用与机制研究

Polypoid choroidal vasculopathy is an important disease to cause blinding eye in Asia's elderly population . Studies have shown that 84.4% of the PCV appeared with abnormal branching choroidal vascular network (BVN), the presence of BVN is an important reason for the recurrence of the disease. How to promote the regression and fibrosis of BVN is a key issue to curb the progression and treatment of PCV. Our previous study found that hepatocyte growth factor (HGF), and eotaxin-2 were increased in body fluids of patients with PCV, and HGF and ecotaxin-2 may be involved in the proliferation and migration of vascular endothelial cells via Notch / Dll4, we speculate that the mechanisms involved regulating the formation and fibrosis in BVN of PCV. The project intends to pass hHTRA1 + PCV transgenic mouse model and Transwell co-cultured RPE cells and choroidal vascular cell systems endothelium, studied the effect of expression of HGF, anti-VEGF and anti-HGF with formation of the BVN, and the changes of Notch / Dll4, eotaxin-2 and other related factors to define the role of HGF in regulation of BVN’s formation and fibrosis ,which may find a new way to the prevent PCV .

息肉状脉络膜血管病变是亚洲老年人群重要的致盲性眼病。研究显示84.4%的PCV存在异常分支状脉络膜血管网（BVN），BVN的存在是该病复发的重要原因，促进BVN的消退与纤维化是遏制PCV病程进展和治疗的关键问题。我们前期研究发现肝细胞生长因子（HGF）和eotaxin-2均在PCV患者血清和房水中升高，且HGF和ecotaxin-2均可通过Notch/Dll4参与血管内皮细胞的增殖和迁移，我们推测该机制参与调控PCV中BVN的形成和纤维化。本项目拟通过hHTRA1+ 转基因PCV鼠模型和Transwell共培养RPE细胞和脉络膜血管内皮细胞体系，研究过表达HGF、抗VEGF及抗HGF对BVN的形成、纤维化的影响，以及此过程中Notch/Dll4、eotaxin-2等相关因子的变化，以明确HGF在调控BVN形成和纤维化中的作用和机制，为PCV的防治寻找新的途径。

息肉状脉络膜血管病变（PCV）是亚洲老年人群重要的致盲性眼病。研究显示84.4%的PCV存在异常的脉络膜新生血管（BVN），属于脉络膜新生血管（CNV）的一种，是该病复发的重要原因。促进CNV的消退与纤维化是遏制PCV病程进展和治疗的关键问题。本项目利用Transwell共培养RPE细胞和RF/6A细胞建立缺氧模型，通过siRNA抑制RPE细胞中HGF表达以及外源性重组蛋白HGF处理，发现HGF可以促进RF/6A细胞增殖、迁移和血管形成能力。根据mRNA及免疫荧光结果，此过程中伴随Vimentin、SMA、IL-10、IL-6等多种内皮成纤维细胞标记物及炎症因子增加，提示与炎症和纤维化过程密切相关。且在JR5888基因突变CNV小鼠模型中给予抗HGF、抗VEGF、抗TLR2治疗和p38MAPK抑制剂可以降低炎症反应，减少病灶形成的同时降低病灶纤维化过程，提示TLR及MAPK调控了HGF介导的NOTCH通路，参与了脉络膜新生血管形成和纤维化过程，为PCV的防治寻找了新的途径。