Lysophosphatidic Acid Signaling Protects Pulmonary Vasculature From Hypoxia-Induced Remodeling

Objective—Lysophosphatidic acid (LPA) is a bioactive lipid molecule produced by the plasma lysophospholipase D enzyme autotaxin that is present at ≥100 nmol/L in plasma. Local administration of LPA promotes systemic arterial remodeling in rodents. To determine whether LPA contributes to remodeling of the pulmonary vasculature, we examined responses in mice with alterations in LPA signaling and metabolism.Methods and Results—Enpp2+/−mice, which are heterozygous for the autotaxin-encoding gene and which have reduced expression of autotaxin/lysophospholipase D and approximately half normal plasma LPA, were hyperresponsive to hypoxia-induced vasoconstriction and remodeling, as evidenced by the development of higher right ventricular (RV) systolic pressure, greater decline in peak flow velocity across the pulmonary valve, and a higher percentage of muscularized arterioles. Mice lacking LPA1and LPA2, 2 LPA receptors abundantly expressed in the vasculature, also had enhanced hypoxia-induced pulmonary remodeling. With age,Lpar1−/−2−/−mice spontaneously developed elevated RV systolic pressure and RV hypertrophy that was not observed inLpar1−/−mice orLpar2−/−mice. Expression of endothelin-1, a potent vasoconstrictor, was elevated in lungs ofLpar1−/−2−/−mice, and expression of endothelinBreceptor, which promotes vasodilation and clears endothelin, was reduced inEnpp2+/−andLpar1−/−2−/−mice.Conclusion—Our findings indicate that LPA may negatively regulate pulmonary vascular pressure through LPA1and LPA2receptors and that in the absence of LPA signaling, upregulation in the endothelin system favors remodeling.