title: Lysophosphatidic acid-induced arterial wall remodeling: requirement of PPARgamma 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 gamma (PPARgamma). 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 PPARgamma 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 1h without injury into the carotid arteries of LPA(1), LPA(2), LPA(1&2) double knockout, and Mx1Cre-inducible conditional PPARgamma knockout mice targeted to vascular smooth muscle cells, macrophages, and endothelial cells. The neointima was quantified and also stained for CD31, CD68, CD11b, and alpha-smooth muscle actin markers. In LPA(1), LPA(2), LPA(1&2) GPCR knockout, Mx1Cre transgenic, PPARgamma(fl/-), and uninduced Mx1CrexPPARgamma(fl/-) mice AGP- and ROSI-elicited neointima was indistinguishable in its progression and cytological features from that of WT C57BL/6 mice. In PPARgamma(-/-) 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 the balloon injury- and the non-injury chemically-induced neointima. The present data provide genetic evidence for the requirement of PPARgamma 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 alpha-smooth muscle actin.
authors.affiliation: Department of Physiology, University of Tennessee Health Science Center, 894 Union Ave., Suite 426, Memphis, TN 38163, USA.
authors.forename: Yunhui
authors.initials: Y
authors.lastname: Cheng
authors.forename: Natalia
authors.initials: N
authors.lastname: Makarova
authors.forename: Ryoko
authors.initials: R
authors.lastname: Tsukahara
authors.forename: Huazhang
authors.initials: H
authors.lastname: Guo
authors.forename: E
authors.initials: E
authors.lastname: Shuyu
authors.forename: Patricia
authors.initials: P
authors.lastname: Farrar
authors.forename: Louisa
authors.initials: L
authors.lastname: Balazs
authors.forename: Chunxiang
authors.initials: C
authors.lastname: Zhang
authors.forename: Gabor
authors.initials: G
authors.lastname: Tigyi
mesh_terms: D000818:Animals; D020212:Carotid Artery Injuries / Q000188:drug therapy* / Q000473:pathology; D017536:Carotid Artery, Common / Q000187:drug effects* / Q000473:pathology / Q000648:ultrastructure; D055785:Gene Knockdown Techniques; D005994:Glycerophosphates / Q000627:therapeutic use; D007004:Hypoglycemic Agents / Q000627:therapeutic use; D008246:Lysophospholipids / Q000378:metabolism / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D047495:PPAR gamma / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism*; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000627:therapeutic use
chemical_list: D005994:Glycerophosphates; D007004:Hypoglycemic Agents; D008246:Lysophospholipids; D047495:PPAR gamma; D043562:Receptors, G-Protein-Coupled; D045162:Thiazolidinediones; D000077154:Rosiglitazone; C032881:lysophosphatidic acid