Lysophosphatidic acid signaling protects pulmonary vasculature from hypoxia-induced remodeling

Hsin Yuan Cheng, Anping Dong, Manikandan Panchatcharam, Paul Mueller, Fanmuyi Yang, Zhenyu Li, Gordon Mills, Jerold Chun, Andrew J. Morris, Susan S. Smyth

Research output: Contribution to journalArticlepeer-review

21 Scopus citations

Abstract

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 LPA 1 and LPA 2, 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 in Lpar1 -/- mice or Lpar2 -/- mice. Expression of endothelin-1, a potent vasoconstrictor, was elevated in lungs of Lpar1 -/-2 -/- mice, and expression of endothelinB receptor, which promotes vasodilation and clears endothelin, was reduced in Enpp2 +/- and Lpar1 -/-2 -/- mice. Conclusion-: Our findings indicate that LPA may negatively regulate pulmonary vascular pressure through LPA 1 and LPA 2 receptors and that in the absence of LPA signaling, upregulation in the endothelin system favors remodeling.

Original languageEnglish (US)
Pages (from-to)24-32
Number of pages9
JournalArteriosclerosis, thrombosis, and vascular biology
Volume32
Issue number1
DOIs
StatePublished - Jan 2012
Externally publishedYes

Keywords

  • autotaxin
  • lipids
  • lysophospahtidic acid
  • pulmonary artery
  • pulmonary hypertension

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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