Structured 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 (S1P). 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 development and human disease.
Approach and results
We developed mouse models with selective LPP3 deficiency in endothelial and hematopoietic cells. Tyrosine kinase Tek (Tie2) promoter-mediated inactivation of Ppap2b resulted in embryonic lethality due to vascular defects. LPP3 deficiency in adult mice, achieved using a tamoxifen-inducible Cre transgene under the control of the Tie2 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.
Journal of Lipid Research Volume 54, 20132775 systems encompasses species with both ester and ether linkages [(the latter of which are collectively termed alkyl glycerol phosphates (AGP)] as well as differences in hydrocarbon chain length and saturation ( 1 ). LPAs exhibit a broad range of biological activities that are initiated by LPA selective G-protein-coupled cell-surface receptors. Some LPA responses may also be mediated by the nuclear peroxisome proliferator ␥ receptor and the receptor for advanced glycan end products ( 2 ). LPA is present in blood plasma ( 3 ) and accumulates in human atheromas and in experimentally induced atherosclerotic lesions in mice ( 4 ). Studies using LPA receptor-defi cient mice and LPAdirected small molecule therapeutics identify roles for LPA signaling in atherothrombosis and vascular injury responses ( 5-7 ). A common variant in the PPAP2B gene encoding the LPA inactivating cell surface integral membrane enzyme lipid phosphate phosphatase 3 (LPP3) may predict LPP3 mRNA expression in blood cells and is strongly associated with increased human cardiovascular disease risk. In mice, PPAP2B expression in vascular smooth muscle cells is protective against vascular injury responses ( 6, 8 ). Together, these studies point to an important role for LPA in human cardiovascular disease and focus attention on the Lysophosphatidic acid (LPA) denotes a family of radyl hydrocarbon-substituted derivatives of glycerol 3-phosphate. Structural diversity in LPA species identifi ed in biological
Lysophosphatidic acid and sphingosine 1-phosphate are bioactive lipid mediators with potent effects on cardiovascular development and vascular function. New studies define dynamic mechanisms that maintain physiologically relevant levels of both lipids in the blood. We review the mechanisms controlling the production, metabolism, and distribution of these lipids between vascular cells, circulating blood components and the plasma.
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