title: Endothelial lipid phosphate phosphatase-3 deficiency that disrupts the endothelial barrier function is a modifier of cardiovascular development.
abstract: Lipid phosphate phosphatase-3 (LPP3) is expressed at high levels in endothelial cells (ECs). Although LPP3 is known to hydrolyse the phosphate group from lysolipids such as spingosine-1-phosphate and its structural homologues, the function of Lpp3 in ECs is not completely understood. In this study, we investigated how tyrosine-protein kinase receptor (TEK or Tie2) promoter-dependent deletion of Lpp3 alters EC activities.
  
  
  
  Lpp3(fl/fl) mice were crossed with the tg.Tie2(Cre) transgenic line. Vasculogenesis occurred normally in embryos with Tie2(Cre)-mediated deletion of Lpp3 (called Lpp3(ECKO)), but embryonic lethality occurred in two waves, the first wave between E8.5 and E10.5, while the second between E11.5 and E13.5. Lethality in Lpp3(ECKO) embryos after E11.5 was accompanied by vascular leakage and haemorrhage, which likely resulted in insufficient cardiovascular development. Analyses of haematoxylin- and eosin-stained heart sections from E11.5 Lpp3(ECKO) embryos showed insufficient heart growth associated with decreased trabeculation, reduced growth of the compact wall, and absence of cardiac cushions. Staining followed by microscopic analyses of Lpp3(ECKO) embryos revealed the presence of apoptotic ECs. Furthermore, Lpp3-deficient ECs showed decreased gene expression and protein levels of Cyclin-D1, VE-cadherin, Fibronectin, Klf2, and Klf4. To determine the underlying mechanisms of vascular leakage and barrier disruption, we performed knockdown and rescue experiments in cultured ECs. LPP3 knockdown decreased transendothelial electrical resistance and increased permeability. Re-expression of β-catenin cDNA in LPP3-knockdown ECs partially restored the effect of the LPP3 loss, whereas re-expression of p120ctn cDNA did not.
  
  
  
  These findings demonstrate the essential roles of LPP3 in the maturation of EC barrier integrity and normal cardiovascular development.
authors.affiliation: Department of Pharmacology, University of Illinois, 835 S. Wolcott Avenue, Room E403, Chicago, IL 60612, USA.
authors.forename: Ishita
authors.initials: I
authors.lastname: Chatterjee
authors.affiliation: Department of Pharmacology, University of Illinois, 835 S. Wolcott Avenue, Room E403, Chicago, IL 60612, USA.
authors.forename: Jugajyoti
authors.initials: J
authors.lastname: Baruah
authors.affiliation: Department of Pharmacology, University of Illinois, 835 S. Wolcott Avenue, Room E403, Chicago, IL 60612, USA.
authors.forename: Erin E
authors.initials: EE
authors.lastname: Lurie
authors.affiliation: Department of Pharmacology, University of Illinois, 835 S. Wolcott Avenue, Room E403, Chicago, IL 60612, USA kkwary@uic.edu.
authors.forename: Kishore K
authors.initials: KK
authors.lastname: Wary
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism; D017209:Apoptosis; D001808:Blood Vessels / Q000196:embryology / Q000201:enzymology* / Q000473:pathology; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D002199:Capillary Permeability; D051177:Catenins / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D017097:Electric Impedance; D042783:Endothelial Cells / Q000201:enzymology* / Q000473:pathology; D005353:Fibronectins / Q000235:genetics / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D005838:Genotype; D005865:Gestational Age; D006321:Heart / Q000196:embryology; D000090062:Kruppel-Like Factor 4; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018919:Neovascularization, Physiologic; D010641:Phenotype; D010711:Phosphatidate Phosphatase / Q000172:deficiency* / Q000235:genetics; D034622:RNA Interference; D042787:Receptor, TIE-2 / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism; D000095002:Delta Catenin; D000099152:Cadherin 5
chemical_list: D015703:Antigens, CD; D015820:Cadherins; D051177:Catenins; D005353:Fibronectins; D000090062:Kruppel-Like Factor 4; D010711:Phosphatidate Phosphatase; D042787:Receptor, TIE-2; D051176:beta Catenin; D000095002:Delta Catenin; D000099152:Cadherin 5; C495267:CTNNB1 protein, mouse; C000715468:Klf4 protein, mouse; C079086:Tek protein, mouse; C479566:Plpp3 protein, mouse; C000722349:Ctnnd1 protein, mouse
keywords: Beta-catenin; LPP3; Neovascularization; PPAP2b; VE-cadherin