Targeting VEGF-A/VEGFR2 Y949 Signaling-Mediated Vascular Permeability Alleviates Hypoxic Pulmonary Hypertension
Targeting VEGF-A/VEGFR2 Y949 Signaling-Mediated Vascular Permeability Alleviates Hypoxic Pulmonary Hypertension
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DOI：
10.1161/circulationaha.122.061900
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发表时间：
2022-11
期刊：
影响因子：
37.8
通讯作者：
Weibin Zhou;Ke-fang Liu;L. Zeng;Jiaqi He;Xin-bo Gao;X. Gu;Xun Chen;Jing Jing Li-Jing;
中科院分区：
文献类型：
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作者：
Weibin Zhou;Ke-fang Liu;L. Zeng;Jiaqi He;Xin-bo Gao;X. Gu;Xun Chen;Jing Jing Li-Jing;
背景资料：肺动脉高压（PH）与VEGF-A（血管内皮生长因子A）及其受体VEGFR 2（血管内皮生长因子2）表达增加有关，但VEGF-A信号激活是否以及如何参与PH的发病机制尚不清楚。研究方法：在来自PH患者和暴露于缺氧的小鼠的肺样品中研究VEGF-A/VEGFR 2信号激活和VEGFR 2 Y 949依赖性血管渗漏。为了研究它们在缺氧PH中的机制作用，我们检查了携带苯丙氨酸基因敲入的突变小鼠（取代了VEGFR 2残基949处的酪氨酸）（Vefgr 2 Y 949 F）和慢性缺氧暴露后条件性内皮缺失Vegfr 2的小鼠的右心室收缩压、右心室肥大和肺血管病变。结果如下：我们发现PH导致患者和缺氧小鼠的过度肺血管渗漏，这是因为过度激活的VEGF-A/VEGFR 2 Y 949信号轴。在缺氧PH的情况下，内皮细胞中Yes 1和c-Src的激活以及随后的VE-钙粘蛋白磷酸化参与VEGFR 2 Y 949诱导的血管通透性。通过Vefgr 2 Y 949 F点突变消除VEGFR 2 Y 949信号传导足以防止肺血管通透性并抑制缺氧暴露下平滑肌细胞中的巨噬细胞浸润和Rac 1活化，从而导致PH表现减轻，包括远端肺小动脉的肌化、右心室收缩压升高和右心室肥大。重要的是，我们发现，VEGFR 2 Y 949信号在骨髓细胞，包括巨噬细胞是微不足道的，并为缺氧诱导的血管异常和PH的风险。与选择性阻断VEGFR 2 Y 949信号，破坏整个VEGFR 2信号的条件性内皮缺失的Vegfr 2促进PH的发展。结论：我们的研究结果支持VEGF-A/VEGFR 2 Y 949依赖的血管通透性是PH发病机制中的重要决定因素的观点，并可能作为这种疾病的有吸引力的治疗靶点途径。
Background: Pulmonary hypertension (PH) is associated with increased expression of VEGF-A (vascular endothelial growth factor A) and its receptor, VEGFR2 (vascular endothelial growth factor 2), but whether and how activation of VEGF-A signal participates in the pathogenesis of PH is unclear. Methods: VEGF-A/VEGFR2 signal activation and VEGFR2 Y949–dependent vascular leak were investigated in lung samples from patients with PH and mice exposed to hypoxia. To study their mechanistic roles in hypoxic PH, we examined right ventricle systolic pressure, right ventricular hypertrophy, and pulmonary vasculopathy in mutant mice carrying knock-in of phenylalanine that replaced the tyrosine at residual 949 of VEGFR2 (Vefgr2Y949F) and mice with conditional endothelial deletion of Vegfr2 after chronic hypoxia exposure. Results: We show that PH leads to excessive pulmonary vascular leak in both patients and hypoxic mice, and this is because of an overactivated VEGF-A/VEGFR2 Y949 signaling axis. In the context of hypoxic PH, activation of Yes1 and c-Src and subsequent VE-cadherin phosphorylation in endothelial cells are involved in VEGFR2 Y949-induced vascular permeability. Abolishing VEGFR2 Y949 signaling by Vefgr2Y949F point mutation was sufficient to prevent pulmonary vascular permeability and inhibit macrophage infiltration and Rac1 activation in smooth muscle cells under hypoxia exposure, thereby leading to alleviated PH manifestations, including muscularization of distal pulmonary arterioles, elevated right ventricle systolic pressure, and right ventricular hypertrophy. It is important that we found that VEGFR2 Y949 signaling in myeloid cells including macrophages was trivial and dispensable for hypoxia-induced vascular abnormalities and PH. In contrast with selective blockage of VEGFR2 Y949 signaling, disruption of the entire VEGFR2 signaling by conditional endothelial deletion of Vegfr2 promotes the development of PH. Conclusions: Our results support the notion that VEGF-A/VEGFR2 Y949–dependent vascular permeability is an important determinant in the pathogenesis of PH and might serve as an attractive therapeutic target pathway for this disease.