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Lysophosphatidic acid signaling protects pulmonary vasculature from hypoxia-induced remodeling.

ABSTRACT: 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.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.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.

SUBMITTER: Cheng HY

PROVIDER: S-EPMC3241874 | biostudies-literature | 2012 Jan

REPOSITORIES: biostudies-literature

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Lysophosphatidic acid signaling protects pulmonary vasculature from hypoxia-induced remodeling.

Cheng Hsin-Yuan HY Dong Anping A Panchatcharam Manikandan M Mueller Paul P Yang Fanmuyi F Li Zhenyu Z Mills Gordon G Chun Jerold J Morris Andrew J AJ Smyth Susan S SS

Arteriosclerosis, thrombosis, and vascular biology 20111020 1

<h4>Objective</h4>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.<h4>Methods and results</h4>Enpp2(+/-) mice, which are heterozygous for the autotaxi ...[more]

PMID: 22015657

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Project description:The Notch signaling pathway participates in pulmonary artery smooth muscle cell (PASMC) proliferation and apoptosis. Astragaloside IV (AS‑IV) is an effective antiproliferative treatment for vascular diseases. The present study aimed to investigate the protective effects and mechanisms underlying AS‑IV on hypoxia‑induced PASMC proliferation and pulmonary vascular remodeling in pulmonary arterial hypertension (PAH) model rats. Rats were divided into the following four groups: i) normoxia; ii) hypoxia (10% O2); iii) treatment, hypoxia + intragastrical administration of AS‑IV (2 mg/kg) daily for 28 days; and iv) DAPT, hypoxia + AS‑IV treatment + subcutaneous administration of DAPT (10 mg/kg) three times daily. The effects of AS‑IV treatment on the development of hypoxia‑induced PAH, right ventricle (RV) hypertrophy and pulmonary vascular remodeling were examined. Furthermore, PASMCs were treated with 20 µmol/l AS‑IV under hypoxic conditions for 48 h. To determine the effect of Notch signaling in vascular remodeling and the potential mechanisms underlying AS‑IV treatment, 5 mmol/l γ‑secretase inhibitor [N‑[N‑(3,5‑difluorophenacetyl)‑L‑alanyl]‑S‑phenylglycine t‑butyl ester (DAPT)] was used. Cell viability and apoptosis were determined by performing the MTT assay and flow cytometry, respectively. Immunohistochemistry was conducted to detect the expression of proliferating cell nuclear antigen (PCNA). Moreover, the mRNA and protein expression levels of Notch‑3, Jagged‑1, hes family bHLH transcription factor 5 (Hes‑5) and PCNA were measured via reverse transcription‑quantitative PCR and western blotting, respectively. Compared with the normoxic group, hypoxia‑induced PAH model rats displayed characteristics of PAH and RV hypertrophy, whereas AS‑IV treatment alleviated PAH and prevented RV hypertrophy. AS‑IV also inhibited hypoxia‑induced pulmonary vascular remodeling, as indicated by reduced wall thickness and increased lumen diameter of pulmonary arterioles, and decreased muscularization of distal pulmonary vasculature in hypoxia‑induced PAH model rats. Compared with normoxia, hypoxia promoted PASMC proliferation in vitro, whereas AS‑IV treatment inhibited hypoxia‑induced PASMC proliferation by downregulating PCNA expression in vitro and in vivo. In hypoxia‑treated PAH model rats and cultured PASMCs, AS‑IV treatment reduced the expression levels of Jagged‑1, Notch‑3 and Hes‑5. Furthermore, Notch signaling inhibition via DAPT significantly inhibited the pulmonary vascular remodeling effect of AS‑IV in vitro and in vivo. Collectively, the results indicated that AS‑IV effectively reversed hypoxia‑induced pulmonary vascular remodeling and PASMC proliferation via the Notch signaling pathway. Therefore, the present study provided novel insights into the mechanism underlying the use of AS‑IV for treatment of vascular diseases, such as PAH.

Project description:BACKGROUND:In the extracellular environment, lysophosphatidic acid (LPA) species are generated via autotaxin (ATX)-mediated hydrolysis of lysophospholipid precursors. Members of the LPA family are potent lipid mediators transmitting signals via six different G protein-coupled LPA receptors (LPAR1-6). The LPA signaling axis is indispensable for brain development and function of the nervous system; however, during damage of the central nervous system, LPA levels can increase and aberrant signaling events counteract brain function. Here, we investigated regulation of the ATX/LPA/LPAR axis in response to lipopolysaccharide-induced systemic inflammation in mice and potential neurotoxic polarization programs in LPA-activated primary murine microglia. METHODS:In vivo, LPAR1-6 expression was established by qPCR in whole murine brain homogenates and in FACS-sorted microglia. ELISAs were used to quantitate LPA concentrations in the brain and cyto-/chemokine secretion from primary microglia in vitro. Transcription factor phosphorylation was analyzed by immunoblotting, and plasma membrane markers were analyzed by flow cytometry. We used MAPK inhibitors to study signal integration by the JNK, p38, and ERK1/2 branches in response to LPA-mediated activation of primary microglia. RESULTS:Under acute and chronic inflammatory conditions, we observed a significant increase in LPA concentrations and differential regulation of LPAR, ATX (encoded by ENPP2), and cytosolic phospholipase A2 (encoded by PLA2G4A) gene expression in the brain and FACS-sorted microglia. During pathway analyses in vitro, the use of specific MAPK antagonists (SP600125, SB203580, and PD98059) revealed that JNK and p38 inhibition most efficiently attenuated LPA-induced phosphorylation of proinflammatory transcription factors (STAT1 and -3, p65, and c-Jun) and secretion of IL-6 and TNF?. All three inhibitors decreased LPA-mediated secretion of IL-1?, CXCL10, CXCL2, and CCL5. The plasma membrane marker CD40 was solely inhibited by SP600125 while all three inhibitors affected expression of CD86 and CD206. All MAPK antagonists reduced intracellular COX-2 and Arg1 as well as ROS and NO formation, and neurotoxicity of microglia-conditioned media. CONCLUSION:In the present study, we show that systemic inflammation induces aberrant ATX/LPA/LPAR homeostasis in the murine brain. LPA-mediated polarization of primary microglia via MAPK-dependent pathways induces features reminiscent of a neurotoxic phenotype.

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Lysophosphatidic acid signaling protects pulmonary vasculature from hypoxia-induced remodeling.

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Lysophosphatidic acid signaling protects pulmonary vasculature from hypoxia-induced remodeling.

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