新型VEGF Trap抗肿瘤药阿柏西普致高血压的作用及分子机制

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.

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。

本课题系统地揭示了新型靶向VEGF-trap类和酪氨酸激酶抑制剂（TKI）类药物通过血管内皮稳态失衡所致高血压的作用并详细阐明调控网络及关键分子。.1）我们发现：阿柏西普可致内皮依赖性血管舒张功能障碍和高血压，其机制与抑制CAT-1/Akt/eNOS/NO信号转导、ET-1水平升高和ROS积聚有关。补充左旋精氨酸可缓解血管功能损害和高血压；2）仑伐替尼通过磷酸化YAP，减少YAP在细胞核中的表达，进而通过降低GPX4、HO-1、SAT-1和FTH-1 的转录和表达，诱导内皮细胞铁死亡，引起内皮功能障碍，最终导致高血压；3）舒尼替尼引起胰岛素抵抗并抑制IRS-1/AKT/eNOS/NO信号传导，进而引起小鼠血压升高，内皮依赖性血管舒张功能障碍，eNOS活性下降，ROS激活；4）舒尼替尼通过抑制IP3R1磷酸化诱导MAMs下降，导致NO合成减少，线粒体功能障碍，血管舒张功能障碍，血压升高。.另外，课题拓展其他病理因素导致血管损伤，高血压的机制：1）ENaC特异阻断剂苯扎明可抑制高脂诱导的内皮功能障碍和动脉粥样硬化，并揭示其机制；2）揭示环孢霉素（CsA）通过脂质依赖的氧化应激，调节ENaC表达同时激活ENaC诱发高血压的机制；3）发现寒冷刺激致血浆中醛固酮水平显著升高，并通过其受体及其下游信号通路促进内皮ENaC表达及活性的机制；4）揭示同型半胱氨酸通过ROS/COX-2/Sgk1通路促进ENaC活性，进而导致血管内皮舒张功能障碍；5）发现高盐致血清和血管BMP4水平升高通过p38 MAPK/Sgk1/Nedd4-2信号通路使内皮ENaC异常激活进而引起内皮依赖性舒张功能障碍并导致高血压。.本课题首次在功能学层面揭示：TKI类药物通过引起血管内皮稳态失衡和重构导致高血压的作用及分子调控网络，为TKI类药物引起的高血压提供新防治的理论基础和干预靶点。.项目组已经发表标注课题号的（81870370）SCI收录文章，包括Acta Pharmacol Sin, Biochim Biophys Acta Mol Basis Dis, Br J Pharmacol等文章14篇，其中10分 > IF > 5分 10篇。以专家组组长身份编写专家共识2部，以专家组成员参与编写专家共识3部。培养博士后15名，博士后出站5人，培养博士19人，硕士13人，其中博士毕业11人，硕士毕业5人。

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