新型VEGF Trap阿柏西普对肠癌疗效显著，但其所致的高血压严重影响其临床应用和患者预后。然而，阿柏西普致高血压的分子机制不明。在前期工作中发现：阿柏西普使小鼠血压迅速升高，趋化因子CXCL2表达显著升高，炎症因子和黏附因子显著增高，NOX2表达显著升高及ROS聚集，血管功能障碍和结构重构。因此，我们假设：阿柏西普激活内皮和炎症细胞的CXCL2/CXCR2轴，上调内皮NOX2或间接通过Rac1激活NOX2使ROS在血管中聚集，并趋化炎症细胞使其释放炎症因子，而诱导内皮细胞功能障碍，最终导致血管结构性重构和高血压。本项目拟应用野生型和CXCR2基因敲除小鼠及原代培养的小鼠动脉内皮细胞为研究模型，结合血流动力学、影像学、药理学、基因沉默和分子生物学等方法，揭示阿柏西普诱导血管功能/结构重构和高血压的作用及分子调控机制，为其临床合理应用提供理论依据，并为防治其诱导的高血压提供潜在的干预靶点。

Aflibercept, a newly VEGF Trap, is a potent therapeutic reagent for curing colorectal cancer. However, it often causes severe hypertension which limits the clinical usage and interferes with the prognosis of patients. In addition, the underlying mechanisms by which aflibercept leads to hypertension have never been understood. The results obtained from our preliminary studies demonstrated that upon injection of aflibercept, the blood pressure of mice increased rapidly, with a time-dependent manner. The expression levels of CXC motif chemokine ligand 2 (CXCL2), inflammatory factors and adhesion factors were significantly increased in aflibercept-treated mice. Moreover, NOX2 expression was elevated in these mice which may subsequently lead to accumulation of ROS in the artery. Additionally, endothelial-dependent vascular relaxation was also impaired by aflibercept. Surprisingly, five doses injection of mice with aflibercept led to vascular remodeling. According to the results ascribed above, we hypothesize that aflibercept leads to endothelial dysfunction, vascular remodeling and hypertension through following mechanisms: 1) aflibercept activates the CXCL2/CXC chemokine receptor 2 (CXCL2/CXCR2) axis in endothelial cells, thereby promotes the accumulation of ROS in artery by a direct up-regulation of NOX2 activity or by an indirect way depending on Rac1 activation; 2) aflibercept promotes recruitment of inflammatory cells and the release of pro-inflammatory cytokines by activating CXCL2/CXCR2 axis. We will use wild type C57BL/6J mice, CXCR2 gene knockout (CXCR2-/-) mice, and primary cultured mouse aortic endothelial cells to decipher the potential mechanisms by which aflibercept causes vascular dysfunction, remodeling, and hypertension, in combination with a variety of experimental approaches. Our results may shed a light for theoretical basis of clinical rational use of aflibercept and may provide the potential therapeutic targets for preventing and curing aflibercept-induced hypertension.