HIF2α signaling inhibits adherens junctional disruption in acute lung injury
HIF2α signaling inhibits adherens junctional disruption in acute lung injury
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DOI：
10.1172/jci77701
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发表时间：
2015-02-01
影响因子：
15.9
通讯作者：
Malik, Asrar B.
中科院分区：
文献类型：
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作者：
Gong, Haixia;Rehman, Jalees;Malik, Asrar B.
血管内皮屏障功能障碍是诸如急性呼吸窘迫综合征（ARDS）等疾病的基础，其特征在于水肿和炎性细胞浸润。转录因子HIF 2 α在血管内皮细胞（EC）中高度表达，并可调节内皮屏障功能。在这里，我们分析了编码调节粘附连接（AJ）完整性的蛋白质的基因的启动子序列，并确定血管内皮蛋白酪氨酸磷酸酶（VE-PTP）是HIF 2 α的靶点，HIF 2 α诱导的VE-PTP表达增强了VE-钙粘蛋白的去磷酸化，从而减少了VE-钙粘蛋白的内吞作用，从而增强了AJ的完整性和内皮屏障功能。携带Hif 2 α EC特异性缺失的小鼠表现出VE-PTP表达降低和VE-钙粘蛋白磷酸化增加，导致AJs缺陷。内皮细胞中缺乏HIF 2 α的小鼠肺血管通透性和含水量增加，内毒素介导的损伤进一步加剧了这两者。用脯氨酰羟化酶结构域2（PHD 2）抑制剂Fg 4497处理这些小鼠，以缺氧非依赖性方式激活HIF 2 α介导的转录。HIF 2 α激活增加VE-PTP表达，降低VE-钙粘蛋白磷酸化，促进AJ完整性，并防止内皮屏障功能丧失。这些发现表明，HIF 2 α增强内皮屏障的完整性，部分通过VE-PTP表达和所得的VE-钙粘蛋白去磷酸化介导的AJs组装。此外，通过PHD 2抑制激活HIF 2 α/VE-PTP信号传导有可能预防炎症性疾病（如ARDS）中渗漏血管和水肿的形成。
Vascular endothelial barrier dysfunction underlies diseases such as acute respiratory distress syndrome (ARDS), characterized by edema and inflammatory cell infiltration. The transcription factor HIF2 alpha is highly expressed in vascular endothelial cells (ECs) and may regulate endothelial barrier function. Here, we analyzed promoter sequences of genes encoding proteins that regulate adherens junction (AJ) integrity and determined that vascular endothelial protein tyrosine phosphatase (VE-PTP) is a HIF2 alpha target HIF2 alpha-induced VE-PTP expression enhanced dephosphorylation of VE-cadherin, which reduced VE-cadherin endocytosis and thereby augmented AJ integrity and endothelial barrier function. Mice harboring an EC-specific deletion of Hif2 alpha exhibited decreased VE-PTP expression and increased VE-cadherin phosphorylation, resulting in defective AJs. Mice lacking HIF2 alpha in ECs had increased lung vascular permeability and water content, both of which were further exacerbated by endotoxin-mediated injury. Treatment of these mice with Fg4497, a prolyl hydroxylase domain 2 (PHD2) inhibitor, activated HIF2 alpha-mediated transcription in a hypoxia-independent manner. HIF2 alpha activation increased VE-PTP expression, decreased VE-cadherin phosphorylation, promoted AJ integrity, and prevented the loss of endothelial barrier function. These findings demonstrate that HIF2 alpha enhances endothelial barrier integrity, in part through VE-PTP expression and the resultant VE-cadherin dephosphorylation-mediated assembly of AJs. Moreover, activation of HIF2 alpha/VE-PTP signaling via PHD2 inhibition has the potential to prevent the formation of leaky vessels and edema in inflammatory diseases such as ARDS.