Lysophosphatidic acid-induced arterial wall remodeling: Requirement of PPARγ but not LPA1 or LPA2 GPCR

Abstract

Lysophosphatidic acid (LPA) and its ether analog alkyl-glycerophosphate (AGP) elicit arterial wall remodeling when applied intralumenally into the uninjured carotid artery. LPA is the ligand of eight GPCRs and the peroxisome proliferator-activated receptor γ (PPARγ). We pursued a gene knockout strategy to identify the LPA receptor subtypes necessary for the neointimal response in a non-injury model of carotid remodeling and also compared the effects of AGP and the PPARγ agonist rosiglitazone (ROSI) on balloon injury-elicited neointima development. In the balloon injury model AGP significantly increased neointima; however, rosiglitazone application attenuated it. AGP and ROSI were also applied intralumenally for 1 hour without injury into the carotid arteries of LPA 1 , LPA 2 , LPA 1&2 double knockout, and Mx1Cre-inducible conditional PPARγ knockout mice targeted to vascular smooth muscle cells, macrophages, and endothelial cells. The neointima was quantified and also stained for CD31, CD68, CD11b, and α-smooth muscle actin markers. In LPA 1 , LPA 2 , LPA 1&2 GPCR knockouts, Mx1Cre transgenic, PPARγ fl/− , and uninduced Mx1CreXPPARγ fl/− mice AGP-and ROSI-elicited neointima was indistinguishable in its progression and cytological features from that of WT C57BL/6 mice. In PPARγ −/− knockout mice, generated by activation of Mx1Cre-mediated recombination, AGP and ROSI failed to elicit neointima and vascular wall remodeling. Our findings point to a difference in the effects of AGP and ROSI between balloon the injury-and the non-injury chemically-induced neointima. The present data provide genetic evidence for the requirement of PPARγ in AGP-and ROSI-elicited neointimal thickening in the non-injury model and reveal that the overwhelming majority of the cells in the neointimal layer express α-smooth muscle actin.

Lysophosphatidic Acid Receptors LPA 1 and LPA 3 Promote CXCL12-Mediated Smooth Muscle Progenitor Cell Recruitment in Neointima Formation

“…35 In a recent study, neointima formation after 1-AGP incubation of carotid arteries in LPA 1 Ϫ/Ϫ mice was not diminished. 36 However, the potential role of increased LPA 3 expression has not been evaluated in this model. Of note, peroxisome proliferatoractivated receptor (PPAR)-␥ Ϫ/Ϫ mice were protected from 1-AGP-induced neointima formation.…”

“…Of note, peroxisome proliferatoractivated receptor (PPAR)-␥ Ϫ/Ϫ mice were protected from 1-AGP-induced neointima formation. 36 Although we cannot exclude the activation of different signal pathways because of varying 1-AGP concentrations and incubation times used, HIF-1␣-induced activation of PPAR-␥ has been described in cardiac hypertrophy, 37 which may provide a direct link between the prima facie divergent mechanisms. Moreover, LPA20:4-induced PPAR-␥ activation was partially inhibited by the LPA 1/3 antagonist DGPP in vitro indicating the contribution of LPA receptors.…”

Saturated Fatty Acid Palmitate Aggravates Neointima Formation by Promoting Smooth Muscle Phenotypic Modulation

“…11 In line with the effect of LPAs, mice deficient in both LPA1 and LPA2 receptors showed much reduced neointima formation. 39 Thus, lipids are clearly important regulators of SMC phenotype.…”

Lysophosphatidic Acid and Sphingosine-1-Phosphate: A Concise Review of Biological Function and Applications for Tissue Engineering

“…29,32 The effects of PPARg include adipogenic differentiation, lipid metabolism, arterial wall remodeling, 38,39 and dendritic cell differentiation. 40 However, LPA binds strongly at a 3:1 stoichiometric ratio to serum albumin, which serves as a stabilizer and carrier protein.…”