激酶插入结构域受体
血管生成
肺动脉高压
血管内皮生长因子
医学
内科学
血管内皮生长因子A
肺动脉
缺氧(环境)
受体酪氨酸激酶
内皮干细胞
癌症研究
内皮
病理
受体
血管内皮生长因子B
生物
胚胎血管重塑
化学
血管内皮生长因子受体
有机化学
体外
氧气
生物化学
作者
Max‐Paul Winter,Shree Sharma,J Altmann,Veronika Seidl,Adelheid Panzenböck,Arman Alimohammadi,Thomas A. Zelniker,Bassam Redwan,Felix Nagel,David Santer,Alexander Stieglbauer,Bruno K. Podesser,Maria Sibilia,Thomas H. Helbich,Gerald W. Prager,Aysegül Ilhan-Mutlu,Matthias Preusser,Irene Lang
标识
DOI:10.1007/s00395-020-0811-5
摘要
Pulmonary arterial hypertension is a severe and progressive disease characterized by a pulmonary vascular remodeling process with expansion of collateral endothelial cells and total vessel occlusion. Endothelial cells are believed to be at the forefront of the disease process. Vascular endothelial growth factor (VEGF) and its tyrosine kinase receptor, VEGF receptor-2 (VEGFR-2), play a central role in angiogenesis, endothelial cell protection, but also in the destabilization of endothelial barrier function. Therefore, we investigated the consequences of altered VEGF signaling in an experimental model, and looked for translational correlates of this observation in patients. We performed an endothelial cell-specific conditional deletion of the kinase insert domain protein receptor (kdr) gene, coding for VEGFR-2, in C57/BL6 mice (Kdr∆end) and held them in an environmental chamber with 10% FiO2 or under normoxia for 6 weeks. Kdr knockout led to a mild PH phenotype under normoxia that worsened under hypoxia. Kdr∆end mice exhibited a significant increase in pulmonary arterial wall thickness, muscularization, and VEGFR-3+ endothelial cells obliterating the pulmonary artery vessel lumen. We observed the same proliferative vasculopathy in our rodent model as seen in patients receiving anti-angiogenic therapy. Serum VEGF-a levels were elevated both in the experimental model and in humans receiving bevacizumab. Interrupted VEGF signaling leads to a pulmonary proliferative arteriopathy in rodents after direct ablative gene manipulation of Kdr. Histologically, similar vascular lesions can be observed in patients receiving anti-VEGF treatment. Our findings illustrate the importance of VEGF signaling for maintenance of pulmonary vascular patency.
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