Possible Role of Lysophosphatidic Acid in Rat Model of Hypoxic Pulmonary Vascular Remodeling

Abstract

Pulmonary hypertension is characterized by cellular and structural changes in the vascular wall of pulmonary arteries. We hypothesized that lysophosphatidic acid (LPA), a bioactive lipid, is implicated in this vascular remodeling in a rat model of hypoxic pulmonary hypertension. Exposure of Wistar rats to 10% O 2 for 3 weeks induced an increase in the mean serum levels of LPA, to 40.9 (log-detransformed standard deviations: 23.4 -71.7) μM versus 21.6 (11.0-42.3) μM in a matched control animal group (P ¼ 0.037). We also observed perivascular LPA immunohistochemical staining in lungs of hypoxic rats colocalized with the secreted lysophospholipase D autotaxin (ATX). Moreover, ATX colocalized with mast cell tryptase, suggesting implication of these cells in perivascular LPA production. Hypoxic rat lungs expressed more ATX transcripts (2.4-fold) and more transcripts of proteins implicated in cell migration: β2 integrin (1.74-fold), intracellular adhesion molecule 1 (ICAM-1; 1.84-fold), and αM integrin (2.70-fold). Serum from the hypoxic group of animals had significantly higher chemoattractant properties toward rat primary lung fibroblasts, and this increase in cell migration could be prevented by the LPA receptor 1 and 3 antagonists. LPA also increased adhesive properties of human pulmonary artery endothelial cells as well as those of human peripheral blood mononuclear cells, via the activation of LPA receptor 1 or 3 followed by the stimulation of gene expression of ICAM-1, β-1, E-selectin, and vascular cell adhesion molecule integrins. In conclusion, chronic hypoxia increases circulating and tissue levels of LPA, which might induce fibroblast migration and recruitment of mononuclear cells in pulmonary vasculature, both of which contribute to pulmonary vascular remodeling.Keywords: anti-lysophosphatidic acid antibody, fibroblast, circulating progenitor cells, cell migration and adhesion. INTRODUCTIONThe chronic-hypoxia model of pulmonary hypertension (PH) is characterized by an important remodeling of the arteriolar wall. This PH model is very predictable and reproducible, and although implication of vasoconstriction and vasoproliferation of the different cell types constituting the vascular wall has been shown, all the factors involved in these mechanisms are not yet identified. [1][2][3][4] Patients with PH can present with thrombotic pulmonary vascular lesions suggesting abnormalities of blood coagulation factors and platelet function. Hypoxia per se may accelerate blood coagulation 5 and platelet adhesion and aggregation. 6 The activation of platelets can result in the release of multiple and diverse soluble mediators such as

Rosmarinic acid potentiates carnosic acid induced apoptosis in lung fibroblasts

“…In order to see the effect of CA, RA and CA+RA on cell growth and cell migration that is not related to decreased cell viability, we have chosen to study these phenomena at non-cytotoxic concentrations of these substances (5 μM RA and 2 μM CA). Fig 5A displays the results on cell migration and suggests that neither CA, nor RA, nor their combination affected cell motility, while 100 μM DIDS (used as positive control, [ 28 ]) significantly inhibited cell migration (p<0.001 vs control). Same non-cytotoxic concentrations had no significant effect on HLF cell growth ( Fig 5B ).…”

Hypoxia Downregulates LPP3 and Promotes the Spatial Segregation of ATX and LPP1 During Cancer Cell Invasion

“…Increased levels of LPA have been found in malignant effusions from breast, lung, kidney, lymphoma, ovarian and pancreatic cancer patients compared to control groups [6,13,46]. Ascitic fluids from ovarian cancer patients are hypoxic and conditions of hypoxia have been shown to increase LPA levels in non-malignant pathologies [54,55,56], leading to the possibility that hypoxia could be partly responsible for the observed increases in LPA levels in cancers. Here we provide evidence that even though hypoxia enhances the expression of the LPA producing enzyme, ATX in fibrosarcoma HT1080 cells, this effect is cell-specific as no regulation was observed in glioblastoma or breast cancer cells.…”

The phospholipase A2activity of peroxiredoxin 6 modulates NADPH oxidase 2 activationvialysophosphatidic acid receptor signaling in the pulmonary endothelium and alveolar macrophages

“…First, LPAR1‐deficient mice or WT mice treated with the LPAR1 antagonist AM966 showed decreased pulmonary vascular leak in response to bleomycin‐induced lung injury, a response that appeared to result in part from inhibition of NOX2 activation (64, 65). Second, treatment of human pulmonary artery endothelial cells with the LPAR‐1/3 antagonist VPC‐12249 blocks LPA‐induced adhesion of PMNs to an endothelial monolayer (66), although it is not clear that activation of NOX2 is necessary for this effect. Thus, LPAR1 appears to be primarily responsible for the activation of NOX2 in PMVECs.…”