Abstract 17554: Mice with Endothelial-Targeted Inactivation of Ppap2b (Lipid Phosphate Phosphatase 3) Display Enhanced Vascular Inflammation

Abstract

Meta-analysis of data from a series of genome-wide association studies (GWAS) revealed a striking association between the PPAP2B locus and coronary artery disease. The PPAP2B gene encodes for lipid phosphate phosphatase 3 (LPP3), an integral membrane enzyme that dephosphorylates lysophosphatidic acid (LPA), sphingosine 1-phosphate (S1P) and related bioactive lipids. While emerging evidence suggests a role for both LPA and S1P in experimental models of atherosclerosis, essentially nothing is understood about the pathophysiologic role of LPP3, largely due to the fact that genetic deletion results embryonic lethality in mice. We report that constitutive inactivation of LPP3 in vascular endothelial cells accomplished by breeding mice with floxed Ppap2b to mice expressing Cre recombinase under control of the Tie1 promoter results in embryonic lethality and a similar defect in vasculogenesis as is observed in mice with global inactivation of Ppap2b , indicating that dysregulation of LPP3-dependent vascular endothelial cell function likely underlies the developmental phenotype observed in Ppap2b -null embryos. Using an estrogen inducible Cre transgene under control of the Tie1 promoter, we have inactivated Ppap2b expression in endothelial cells in adult mice and confirmed the lack of vascular endothelial LPP3 by immunologic and biochemical approaches. The absence of vascular endothelial LPP3 results in a 2.2 ± 0.5 fold increase in basal vascular permeability, as assessed by Evans blue dye extravasation in lung tissue. The permeability difference is exaggerated following an inflammatory challenge (LPS; 2 mg/kg), and LPS-induced expression of plasma inflammatory markers IL6 and KC are 3.3 ± 0.5 and 1.9 ± 0.6 fold higher in mice lacking endothelial LPP3. In addition, loss of endothelial LPP3 impairs angiogenesis in matrigel implanted in mice. These results demonstrate a fundamental role for LPP3 in maintaining the integrity of the vascular endothelium. Importantly, our findings suggest that polymorphisms associated with a reduction in LPP3 expression could promote vascular inflammation and thereby heighten risk of coronary artery disease and myocardial infarction.