Mice With Targeted Inactivation of Ppap2b in Endothelial and Hematopoietic Cells Display Enhanced Vascular Inflammation and Permeability

Abstract

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.

Translating GWAS Into the Flow-Regulated Modulation of Lipid Mediator Signaling

“…8 Also, the inducible postnatal deletion of Ppap2b resulted in the disruption of endothelial barrier function and impaired angiogenesis. 9 Linking the loss of an LPA inactivating mechanism with endothelial cell activation or inflammation fits well with observations that decreasing LPA production or antagonizing its function are able to preserve barrier function. If an LPA-inactivating molecule is implicated in the endothelial cell response to flow, then its inhibition or downregulation should mimic the effects of disturbed or proatherogenic flow.…”

Lipid phosphate phosphatases and their roles in mammalian physiology and pathology

“…This dynamic expression pattern of LPP3 in vasculature could refl ect its critical role during vascular development ( 106 ). A mouse model with conditional knockout of LPP3 in endothelial and hematopoietic cells shows similar defects in vasculogenesis and embryo death to those in mice with global knockout of LPP3 ( 107 ). The function of LPP3 knockout in endothelial cells of mice was revealed using a tamoxifen-inducible Cre-recombination.…”

“…The function of LPP3 knockout in endothelial cells of mice was revealed using a tamoxifen-inducible Cre-recombination. LPP3 defi ciency in endothelial cells increases vascular permeability and enhanced sensitivity of infl ammation-induced vascular leak, which is restored by blocking LPA production or signals through LPA receptors ( 107 ). LPP3 also attenuates injuryinduced proliferation of carotid artery smooth muscle cells.…”

Serum Autotaxin Levels Are Associated with Proteinuria and Kidney Lesions in Japanese Type 2 Diabetic Patients with Biopsy-proven Diabetic Nephropathy

“…Recently, phosphatidic acid phosphatase type 2B, an integral membrane protein known as lipid phosphate phosphatase-3 that inactivates LPA, was implicated in coronary artery disease by genome-wide association studies (43). LPA has been reported to promote endothelial permeability in culture models and mouse models with selective lipid phosphate phosphatase-3 deficiency (44,45). In addition, it was reported that the endothelial barrier function was restored by the pharmacological or genetic inhibition of either LPA production by the circulating ATX or of Gprotein-coupled receptor-dependent LPA signaling (45).…”