Interruption of vascular endothelial growth factor receptor 2 signaling induces a proliferative pulmonary vasculopathy and pulmonary hypertension
Interruption of vascular endothelial growth factor receptor 2 signaling induces a proliferative pulmonary vasculopathy and pulmonary hypertension
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DOI：
10.1007/s00395-020-0811-5
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发表时间：
2020-09-03
影响因子：
9.5
通讯作者：
Lang, Irene M.
中科院分区：
文献类型：
--
作者：
Winter, Max-Paul;Sharma, Smriti;Lang, Irene M.
肺动脉高压是一种严重的进行性疾病，其特征是伴随侧支内皮细胞扩张和总血管闭塞的肺血管重塑过程。内皮细胞被认为处于疾病过程的最前沿。血管内皮生长因子 (VEGF) 及其酪氨酸激酶受体 VEGF 受体-2 (VEGFR-2) 在血管生成、内皮细胞保护以及内皮屏障功能不稳定中发挥核心作用。因此，我们在实验模型中研究了 VEGF 信号传导改变的后果，并在患者中寻找这一观察结果的转化相关性。我们对 C57/BL6 小鼠（Kdr（增量结束））中编码 VEGFR-2 的激酶插入域蛋白受体 (kdr) 基因进行内皮细胞特异性条件性删除，并将其置于 10% FiO(2) 或常氧条件下的环境室中 6 周。Kdrknockout 导致常氧条件下出现轻微的 PH 表型，而在缺氧条件下会恶化。Kdr( 增量) end)小鼠表现出肺动脉壁厚度、肌化和VEGFR-3(+)内皮细胞显着增加，从而消除了肺动脉血管腔。我们在啮齿动物模型中观察到与接受抗血管生成治疗的患者相同的增殖性血管病变。在实验模型和接受贝伐单抗的人体中，血清 VEGF-a 水平均升高。在直接消融 Kdr 基因操作后，VEGF 信号传导中断会导致啮齿动物出现肺增殖性动脉病。在组织学上，在接受抗 VEGF 治疗的患者中可以观察到类似的血管病变。我们的研究结果说明了 VEGF 信号传导对于维持肺血管通畅的重要性。
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 thekinase insert domain protein receptor(kdr) gene, coding for VEGFR-2, in C57/BL6 mice (Kdr( increment end))and held them in an environmental chamber with 10% FiO(2)or under normoxia for 6 weeks.Kdrknockout led to a mild PH phenotype under normoxia that worsened under hypoxia.Kdr( increment 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 ofKdr.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.