Regulation of the pulmonary vasculature by lysophospholipase D autotaxin - lysophosphatidic acid signaling Public Deposited

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  • March 21, 2019
Creator
  • Cheng, Hsin-Yuan
    • Affiliation: School of Medicine, Department of Cell Biology and Physiology
Abstract
  • Lysophosphatidic acid (LPA) is a bioactive lipid molecule present at physiologically relevant levels in serum that acts by binding to a family of G-protein coupled receptors. Receptor active LPA is produced by the plasma lysophospholipase D enzyme autotaxin/lysoPLD. To define a role for LPA in the pulmonary vasculature, we examined the effect of reduced and elevated circulating LPA in a model of hypoxia-induced pulmonary vasoreactivity. We report that mice carrying one normal and one null allele of the gene encoding autotaxin/lysoPLD (Enpp2+/-), which have ~ half of plasma LPA, are hyper-reactive to hypoxia-induce vasoconstriction and remodeling as evidenced by the development of higher right ventricular systolic pressures, greater decline in peak flow velocity across the pulmonary valve, and a higher percentage of muscularized arteries at three weeks after exposure to hypoxia. Mice overexpressing human Enpp2 transgene (Enpp2-Tg) may be moderately protected from hypoxia-induced pulmonary hypertension with less reduction in peak flow velocity across the pulmonary valve after hypoxia exposure. Because LPA1 and LPA2 receptors are highly expressed in the cardiovascular system and therefore are candidate receptors to mediate the effects of LPA, we examined the pulmonary vasculature of mice lacking LPA 1 and LPA2 (LPA1-/-2-/-). With age, LPA1-/-2-/- mice displayed elevations in right ventricular systolic pressure and developed right ventricular hypertrophy. No differences in pulmonary oxygen saturation, hematocrit, vascular permeability, platelet function, or blood coagulation were observed in LPA1-/-2-/- mice. LPA1-/-2-/- mice had a two-fold decline in peak flow velocity across the pulmonary valve after hypoxia versus wild-type controls, and increased muscularization of the pulmonary arterioles following hypoxia. Taken together, our results suggest that circulating LPA regulates pulmonary vascular pressure by effects on LPA1 and LPA2 receptors.
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  • "... in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Department of Cell and Molecular Physiology."
Advisor
  • Smyth, Susan S.
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  • Chapel Hill, NC
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  • Open access
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