Endothelial Hypoxia-Inducible Factor-2 Is Required for the Maintenance of Airway Microvasculature
Endothelial Hypoxia-Inducible Factor-2 Is Required for the Maintenance of Airway Microvasculature
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DOI：
10.1161/circulationaha.118.036157
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发表时间：
2019-01-22
期刊：
影响因子：
37.8
通讯作者：
Nicolls, Mark R.
中科院分区：
文献类型：
--
作者：
Jiang, Xinguo;Tian, Wen;Nicolls, Mark R.
背景资料：低氧诱导因子（HIF-1和HIF-2）是低氧应激适应性反应的关键介质，在维持肺内环境稳定中起重要作用。人类和动物遗传学研究证实，异常HIF与肺血管病理学和慢性肺部疾病相关，但仍不清楚内皮细胞HIF的产生是否对微血管健康至关重要。大气道有一个理想的循环床，用于评估组织学变化和生理学在转基因marticles.Methods：气管微血管的小鼠，有条件地删除或过表达的HIF-1或HIF-2，进行了评估解剖，灌注和渗透性。血管生成信号研究评估了HIF表达失调引起的血管变化。原位气管移植模型进一步评估了单个HIF亚型在气道内皮cells.Results中的贡献：HIF-2而不是HIF-1的基因缺失导致气管内皮细胞凋亡，减少周细胞覆盖，减少血管灌注，屏障功能缺陷，覆盖上皮异常，和上皮下纤维化重塑。HIF-2通过内皮血管生成素-1/TIE2信号和Notch活性促进气道微血管完整性。在功能性气管移植中，气道供体中HIF-2缺乏加速了移植物微血管损失，而HIF-2或血管生成素-1过表达延长了移植物微血管灌注。增强内皮HIF-2在移植供体促进气道微血管的完整性和减少同种异体免疫inflammation.Conclusions：我们的研究结果表明，内皮HIF-2的组成性表达所需的气道微血管健康。
Background: Hypoxia-inducible factors (HIFs), especially HIF-1 and HIF-2, are key mediators of the adaptive response to hypoxic stress and play essential roles in maintaining lung homeostasis. Human and animal genetics studies confirm that abnormal HIF correlates with pulmonary vascular pathology and chronic lung diseases, but it remains unclear whether endothelial cell HIF production is essential for microvascular health. The large airway has an ideal circulatory bed for evaluating histological changes and physiology in genetically modified rodents.Methods: The tracheal microvasculature of mice, with conditionally deleted or overexpressed HIF-1 or HIF-2, was evaluated for anatomy, perfusion, and permeability. Angiogenic signaling studies assessed vascular changes attributable to dysregulated HIF expression. An orthotopic tracheal transplantation model further evaluated the contribution of individual HIF isoforms in airway endothelial cells.Results: The genetic deletion of Hif-2 but not Hif-1 caused tracheal endothelial cell apoptosis, diminished pericyte coverage, reduced vascular perfusion, defective barrier function, overlying epithelial abnormalities, and subepithelial fibrotic remodeling. HIF-2 promoted microvascular integrity in airways through endothelial angiopoietin-1/TIE2 signaling and Notch activity. In functional tracheal transplants, HIF-2 deficiency in airway donors accelerated graft microvascular loss, whereas HIF-2 or angiopoietin-1 overexpression prolonged transplant microvascular perfusion. Augmented endothelial HIF-2 in transplant donors promoted airway microvascular integrity and diminished alloimmune inflammation.Conclusions: Our findings reveal that the constitutive expression of endothelial HIF-2 is required for airway microvascular health.