Mice With Targeted Inactivation of Ppap2b in Endothelial and Hematopoietic Cells Display Enhanced Vascular Inflammation and Permeability

• DOI: 10.1161/atvbaha.113.302335
• Publication Date: 2014-02-07T02:34:31Z
• Authors: Manikandan Pancha...; Abdel K. Salous; Jason Brandon; Sumitra Miriyala; Jessica Wheeler; Pooja Patil; Manjula Sunkara; Andrew J. Morris; Diana Escalante-A...; Susan S. Smyth
• Keywords: Autotaxin; Vascular permeability

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