Prolyl Hydroxylase Domain-2 Protein Regulates Lipopolysaccharide-Induced Vascular Inflammation

Am J Pathol. 2019 Jan;189(1):200-213. doi: 10.1016/j.ajpath.2018.09.012. Epub 2018 Oct 17.


Acute lung injury and its more severe form, acute respiratory distress syndrome, are life-threatening respiratory disorders. Overwhelming pulmonary inflammation and endothelium disruption are commonly observed. Endothelial cells (ECs) are well recognized as key regulators in leukocyte adhesion and migration in response to bacterial infection. Prolyl hydroxylase domain (PHD)-2 protein, a major PHD in ECs, plays a critical role in intracellular oxygen homeostasis, angiogenesis, and pulmonary hypertension. However, its role in endothelial inflammatory response is unclear. We investigated the role of PHD2 in ECs during endotoxin-induced lung inflammatory responses with EC-specific PHD2 inducible knockout mice. On lipopolysaccharide challenge, PHD2 depletion in ECs attenuates lipopolysaccharide-induced increases of lung vascular permeability, edema, and inflammatory cell infiltration. Moreover, EC-specific PHD2 inducible knockout mice exhibit improved adherens junction integrity and endothelial barrier function. Mechanistically, PHD2 knockdown induces vascular endothelial cadherin in mouse lung microvascular primary endothelial cells. Moreover, PHD2 knockdown can increase hypoxia-inducible factor/vascular endothelial protein tyrosine phosphatase signaling and reactive oxygen species-dependent p38 activation, leading to the induction of vascular endothelial cadherin. Data indicate that PHD2 depletion prevents the formation of leaky vessels and edema by regulating endothelial barrier function. It provides direct in vivo evidence to suggest that PHD2 plays a pivotal role in vascular inflammation. The inhibition of endothelial PHD2 activity may be a new therapeutic strategy for acute inflammatory diseases.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Acute Lung Injury / chemically induced
  • Acute Lung Injury / genetics
  • Acute Lung Injury / immunology*
  • Acute Lung Injury / pathology
  • Alveolar Epithelial Cells / immunology
  • Alveolar Epithelial Cells / pathology
  • Animals
  • Cadherins / genetics
  • Cadherins / immunology
  • Capillary Permeability / drug effects*
  • Capillary Permeability / genetics
  • Capillary Permeability / immunology
  • Cell Adhesion / drug effects
  • Cell Adhesion / genetics
  • Cell Adhesion / immunology
  • Cell Movement / drug effects
  • Cell Movement / genetics
  • Cell Movement / immunology
  • Endothelial Cells / immunology
  • Endothelial Cells / pathology
  • Endothelium, Vascular / immunology*
  • Endothelium, Vascular / pathology
  • Humans
  • Hypoxia-Inducible Factor-Proline Dioxygenases / genetics
  • Hypoxia-Inducible Factor-Proline Dioxygenases / immunology*
  • Inflammation / chemically induced
  • Inflammation / genetics
  • Inflammation / immunology
  • Inflammation / pathology
  • Leukocytes / immunology
  • Leukocytes / pathology
  • Lipopolysaccharides / toxicity*
  • MAP Kinase Signaling System / drug effects
  • MAP Kinase Signaling System / genetics
  • MAP Kinase Signaling System / immunology
  • Male
  • Mice
  • Mice, Transgenic
  • Protein Tyrosine Phosphatases / genetics
  • Protein Tyrosine Phosphatases / immunology
  • United States
  • Vasculitis / chemically induced
  • Vasculitis / genetics
  • Vasculitis / immunology*
  • Vasculitis / pathology
  • p38 Mitogen-Activated Protein Kinases / genetics
  • p38 Mitogen-Activated Protein Kinases / immunology


  • Cadherins
  • Cdh1 protein, mouse
  • Lipopolysaccharides
  • Egln1 protein, mouse
  • Hypoxia-Inducible Factor-Proline Dioxygenases
  • p38 Mitogen-Activated Protein Kinases
  • Protein Tyrosine Phosphatases