Angiogenesis Redux: An Overall Protective Role of VEGF/KDR Signaling in the Microvasculature in Pulmonary Arterial Hypertension.
Angiogenesis Redux: An Overall Protective Role of VEGF/KDR Signaling in the Microvasculature in Pulmonary Arterial Hypertension.
复制标题
血管生成还原：肺动脉高压微血管中 VEGF/KDR 信号传导的总体保护作用。
DOI：
10.1161/atvbaha.123.319839
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发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Yu,PaulB
中科院分区：
文献类型：
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作者：
Zhong,Ying;Yu,PaulB
血管生成一直被认为是影响肺动脉高压（PAH）发病机制的重要因素，但并非没有争议。通过VEGF的血管生成信号转导的假定作用（血管内皮生长因子）及其受体VEGFR 1（VEGF受体1; VEGFR 1/FLT 1 [Fms样酪氨酸激酶1]）和VEGFR 2（血管内皮生长因子受体2; VEGFR 2/FLK 1 [胎肝激酶1]/KDR [激酶插入结构域受体]）PAH的免疫组织学和生物标志物研究最初提出，但最近得到了遗传性PAH中的功能KDR突变。在9月号的ATVB中，Akiyama等1证明Flk 1/Kdr在介导小鼠缺氧诱导的肺动脉高压（PH）进展中的明确作用。作者使用谱系标记来证明Flk 1在肺微血管内皮中的优先表达，其被缺氧血管损伤有力地上调，与Flt 1相反，Flt 1在肺导管和微血管中广泛表达并且不被缺氧诱导。出生后Flk 1的内皮特异性消融显示可引起提示内皮活化的基线肺微血管结构变化，加剧缺氧诱导的中膜肥大和新生内膜形成，并诱导内皮粘附、炎症和增殖信号的广泛失调。这些发现证明了Vegf-Flk 1信号在肺微血管稳态中的保护作用，并为KDR功能丧失突变如何通过内皮激活、炎症和对缺氧损伤的失调反应引起综合征性PAH提供了合理的机制解释（图）。
Angiogenesis has long been postulated to influ-ence the pathogenesis of pulmonary arterial hypertension (PAH) but not without controversy. Putative roles of angiogenic signaling via VEGF (vascular endothelial growth factor) and its receptors VEGFR1 (VEGF receptor 1; VEGFR1/FLT1 [Fms-like tyrosine kinase 1]) and VEGFR2 (VEGF receptor 2; VEGFR2/FLK1 [fetal liver kinase 1]/KDR [kinase insert domain receptor]) in PAH were initially suggested from immune histology and biomarker studies in PAH but more recently have been supported by the identification of loss-of-function KDR mutations in heritable PAH. In the September issue of ATVB, Akiyama et al1 demonstrate a clear role of Flk1/Kdr in mediating the progression of hypoxia-induced pulmonary hypertension (PH) in mice. The authors use lineage marking to demonstrate preferential expression of Flk1 in the pulmonary microvascular endothelium that is potently upregulated by hypoxic vascular injury, in contrast to Flt1, which is broadly expressed in both pulmonary conduit and microvessels and not induced by hypoxia. Postnatal endothelialspecific ablation of Flk1 is shown to cause baseline pulmonary microvascular structural changes suggestive of endothelial activation, exacerbate hypoxia-induced medial hypertrophy and neointima formation, and induce broad dysregulation of endothelial adhesion, inflammatory, and proliferative signaling in these contexts. These findings demonstrate a protective role of Vegf-Flk1 signaling in pulmonary microvascular homeostasis and provide a plausible mechanistic explanation for how lossof-function mutations in KDR may cause syndromic PAH via endothelial activation, inflammation, and dysregulated responses to hypoxic injury (Figure).