title: Mice with targeted inactivation of ppap2b in endothelial and hematopoietic cells display enhanced vascular inflammation and permeability.
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.
  
  
  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.
authors: From the Division of Cardiovascular Medicine, Gill Heart Institute, University of Kentucky, Lexington, KY (M.P., A.K.S., J.B., S.M., J.W., P.P., M.S., A.J.M., S.S.S.); División de Neurociencias, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, México DF, Mexico (E.-A.); and Medical Service, Lexington VA Medical Center, Lexington, KY (A.J.M., S.S.S.).
authors: Manikandan
authors: M
authors: Panchatcharam
authors: Abdel K
authors: AK
authors: Salous
authors: Jason
authors: J
authors: Brandon
authors: Sumitra
authors: S
authors: Miriyala
authors: Jessica
authors: J
authors: Wheeler
authors: Pooja
authors: P
authors: Patil
authors: Manjula
authors: M
authors: Sunkara
authors: Andrew J
authors: AJ
authors: Morris
authors: Diana
authors: D
authors: Escalante-Alcalde
authors: Susan S
authors: SS
authors: Smyth
mesh_terms: D000818:Animals; D002199:Capillary Permeability / Q000187:drug effects; D016207:Cytokines / Q000097:blood; D042783:Endothelial Cells / Q000187:drug effects / Q000201:enzymology*; D005838:Genotype; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000201:enzymology*; D007249:Inflammation / Q000097:blood / Q000201:enzymology* / Q000235:genetics; D018836:Inflammation Mediators / Q000097:blood; D019426:Integrases / Q000235:genetics; D008246:Lysophospholipids / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010641:Phenotype; D010711:Phosphatidate Phosphatase / Q000172:deficiency* / Q000235:genetics; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism; D011401:Promoter Regions, Genetic; D042787:Receptor, TIE-2 / Q000235:genetics; D049368:Receptors, Lysophosphatidic Acid / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction; D019076:Transgenes; D000099189:Lysophospholipase D
chemical_list: D016207:Cytokines; D018836:Inflammation Mediators; D019426:Integrases; D008246:Lysophospholipids; D010711:Phosphatidate Phosphatase; D010727:Phosphoric Diester Hydrolases; D042787:Receptor, TIE-2; D049368:Receptors, Lysophosphatidic Acid; D000099189:Lysophospholipase D; C079086:Tek protein, mouse; C045073:Cre recombinase; C479566:Plpp3 protein, mouse; C032881:lysophosphatidic acid
keywords: autotaxin protein, human; capillary permeability; endothelial cells; hematopoietic stem cells; lysophosphatidic acid