Tie‐2‐Cre‐mediated Inactivation of Lipid phosphate phosphatase (Lpp)‐3 Results in Vascular Defects

Abstract

RationaleMouse embryos with null Lpp3 alleles die as early as E6.5days as they fail to form chorio‐allantoic placenta and yolk‐sac blood vessels. Thus, in vivo function of Lpp3 gene during later stages of embryonic development is not known.GoalTo examine tissue specific function of Lpp3, we generated Lpp3flox/flox mice. To delete Lpp3 in endothelial cell (ECs), we crossed Lpp3flox/flox mice with Tie‐2‐Cre transgenic line.ResultsIn contrast to the conventional Lpp3 deletion, Tie‐2‐Cre mediated Lpp3 deletion in ECs did not affect normal vasculogenesis; however, this led to impaired angiogenesis and late embryonic lethal phenotype. Microscopic analyses revealed reduced fibronectin and VE‐cadherin expression, and increased apoptosis in CD31‐positive vascular structures. Transmission electron microscopy confirmed the presence of apoptotic ECs in mutants. Accordingly, Lpp3 null cells showed increase in p53 and p21 levels, with concomitant decrease in cell proliferation as illustrated by reduced 6‐Bromodeoxyuridine incorporation. In vitro, LPP3 knockdown decreased transendothelial electrical resistance, interestingly re‐expression of β‐catenin cDNA into LPP3 depleted ECs partially restored the effect of loss of LPP3.ConclusionThese results define a critical role of LPP3 in angiogenesis, vascular development and control of apoptotic pathway.Support: NIH R01HL07935, UIC CCTS UL1RR029879.