title: HIF2α signaling inhibits adherens junctional disruption in acute lung injury.
abstract: Vascular endothelial barrier dysfunction underlies diseases such as acute respiratory distress syndrome (ARDS), characterized by edema and inflammatory cell infiltration. The transcription factor HIF2α 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 HIF2α target. HIF2α-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 Hif2a exhibited decreased VE-PTP expression and increased VE-cadherin phosphorylation, resulting in defective AJs. Mice lacking HIF2α 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 HIF2α-mediated transcription in a hypoxia-independent manner. HIF2α activation increased VE-PTP expression, decreased VE-cadherin phosphorylation, promoted AJ integrity, and prevented the loss of endothelial barrier function. These findings demonstrate that HIF2α enhances endothelial barrier integrity, in part through VE-PTP expression and the resultant VE-cadherin dephosphorylation-mediated assembly of AJs. Moreover, activation of HIF2α/VE-PTP signaling via PHD2 inhibition has the potential to prevent the formation of leaky vessels and edema in inflammatory diseases such as ARDS.
authors.forename: Haixia
authors.initials: H
authors.lastname: Gong
authors.forename: Jalees
authors.initials: J
authors.lastname: Rehman
authors.forename: Haiyang
authors.initials: H
authors.lastname: Tang
authors.forename: Kishore
authors.initials: K
authors.lastname: Wary
authors.forename: Manish
authors.initials: M
authors.lastname: Mittal
authors.forename: Pallavi
authors.initials: P
authors.lastname: Chaturvedi
authors.forename: You Yang
authors.initials: YY
authors.lastname: Zhao
authors.forename: Pallavi
authors.initials: P
authors.lastname: Chatturvedi
authors.forename: Youyang
authors.initials: Y
authors.lastname: Zhao
authors.forename: Yulia A
authors.initials: YA
authors.lastname: Komarova
authors.forename: Yulia A
authors.initials: YA
authors.lastname: Komorova
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Vogel
authors.forename: Asrar B
authors.initials: AB
authors.lastname: Malik
mesh_terms: D055371:Acute Lung Injury / Q000378:metabolism* / Q000473:pathology; D022005:Adherens Junctions / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism*; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D042783:Endothelial Cells / Q000378:metabolism* / Q000473:pathology; D015971:Gene Expression Regulation, Enzymologic / Q000235:genetics; D006801:Humans; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D010766:Phosphorylation / Q000235:genetics; D054631:Receptor-Like Protein Tyrosine Phosphatases, Class 3 / Q000096:biosynthesis / Q000235:genetics; D012128:Respiratory Distress Syndrome / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction; D000099152:Cadherin 5; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D015703:Antigens, CD; D051792:Basic Helix-Loop-Helix Proteins; D015820:Cadherins; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; D054631:Receptor-Like Protein Tyrosine Phosphatases, Class 3; D000099152:Cadherin 5; D000099162:Endothelial PAS Domain-Containing Protein 1; C490190:EGLN1 protein, human; C490189:Egln1 protein, mouse