Mice with targeted inactivation of Ppap2b in endothelial and hematopoietic cells display enhanced vascular inflammation and permeability

Manikandan Panchatcharam, Abdel K. Salous, Jason Brandon, Sumitra Miriyala, Jessica Wheeler, Pooja Patil, Manjula Sunkara, Andrew J. Morris, Diana Escalante-Alcalde, Susan S. Smyth

Research output: Contribution to journalArticlepeer-review

66 Scopus citations

Abstract

Objective-Lipid phosphate phosphatase 3 (LPP3), encoded by the PPAP2B gene, is an integral membrane enzyme that dephosphorylates, and thereby terminates, the G-protein-coupled receptor-mediated signaling actions of lysophosphatidic acid (LPA) and sphingosine-1-phosphate. LPP3 is essential for normal vascular development in mice, and a common PPAP2B polymorphism is associated with increased risk of coronary artery disease in humans. Herein, we investigate the function of endothelial LPP3 to understand its role in the development and human disease. Approach and results-We developed mouse models with selective LPP3 deficiency in endothelial and hematopoietic cells. Tyrosine kinase Tek promoter-mediated inactivation of Ppap2b resulted in embryonic lethality because of vascular defects. LPP3 deficiency in adult mice, achieved using a tamoxifen-inducible Cre transgene under the control of the Tyrosine kinase Tek promoter, enhanced local and systemic inflammatory responses. Endothelial, but not hematopoietic, cell LPP3 deficiency led to significant increases in vascular permeability at baseline and enhanced sensitivity to inflammation-induced vascular leak. Endothelial barrier function was restored by pharmacological or genetic inhibition of either LPA production by the circulating lysophospholipase D autotaxin or of G-protein-coupled receptor-dependent LPA signaling. Conclusions-Our results identify a role for the autotaxin/LPA-signaling nexus as a mediator of endothelial permeability in inflammation and demonstrate that LPP3 limits these effects. These findings have implications for therapeutic targets to maintain vascular barrier function in inflammatory states.

Original languageEnglish
Pages (from-to)837-845
Number of pages9
JournalArteriosclerosis, Thrombosis, and Vascular Biology
Volume34
Issue number4
DOIs
StatePublished - Apr 2014

Keywords

  • autotaxin protein
  • capillary permeability
  • endothelial cells
  • hematopoietic stem cells
  • human
  • lysophosphatidic acid

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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