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Lysophosphatidic acid signaling protects pulmonary vasculature from hypoxia-induced remodeling.
Cheng, Hsin-Yuan; Dong, Anping; Panchatcharam, Manikandan; Mueller, Paul; Yang, Fanmuyi; Li, Zhenyu; Mills, Gordon; Chun, Jerold; Morris, Andrew J; Smyth, Susan S.
Afiliación
  • Cheng HY; Division of Cardiovascular Medicine, Gill Heart Institute, University of Kentucky, Lexington, KY, USA.
Arterioscler Thromb Vasc Biol ; 32(1): 24-32, 2012 Jan.
Article en En | MEDLINE | ID: mdl-22015657
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 endothelin(B) receptor, which promotes vasodilation and clears endothelin, was reduced in Enpp2(+/-) and Lpar1(-/-)2(-/-) mice.

CONCLUSIONS:

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.
Asunto(s)

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Arteria Pulmonar / Lisofosfolípidos / Hipoxia Tipo de estudio: Etiology_studies Límite: Animals Idioma: En Revista: Arterioscler Thromb Vasc Biol Asunto de la revista: ANGIOLOGIA Año: 2012 Tipo del documento: Article País de afiliación: Estados Unidos

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Arteria Pulmonar / Lisofosfolípidos / Hipoxia Tipo de estudio: Etiology_studies Límite: Animals Idioma: En Revista: Arterioscler Thromb Vasc Biol Asunto de la revista: ANGIOLOGIA Año: 2012 Tipo del documento: Article País de afiliación: Estados Unidos
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