title: Lysophosphatidic acid receptors LPA1 and LPA3 promote CXCL12-mediated smooth muscle progenitor cell recruitment in neointima formation.
abstract: BACKGROUND
  The chemokine CXCL12 (CXC motif ligand 12) and its receptor CXCR 4 (CXC motif receptor 4) direct the recruitment of smooth muscle progenitor cells (SPCs) in neointima formation after vascular injury. Lysophosphatidic acid (LPA) induces CXCL12 and neointimal accumulation of smooth muscle cells (SMCs) in uninjured arteries. Thus, we hypothesize that LPA may regulate CXCL12-mediated vascular remodelling.
  
  
  OBJECTIVE
  We evaluated the role of LPA receptors in initiating CXCL12-dependent vascular repair by SPCs.
  
  
  RESULTS
  Wire-induced carotid injury was performed in apolipoprotein E(-/-) mice on western-type diet. LPA receptor expression was studied by immunostaining and quantitative RT-PCR. LPA receptors LPA(1) and LPA(3) were detected in the media of uninjured arteries and in the injury-induced neointima. LPA(3) mRNA was upregulated and LPA(1) mRNA downregulated at one week after injury. The LPA(1/3) antagonist Ki16425 inhibited neointima formation by 71% and reduced both relative neointimal SMCs and the macrophage content. Additionally, neointimal hypoxia-inducible factor-1alpha and CXCL12 expression, the injury-induced peripheral stem cell antigen-1 (Sca-1)(+)/Lin(-) SPC mobilization, and the neointimal recruitment of Sca-1(+)SMCs were inhibited by Ki16425. In wild type mice, LPA20:4 increased CXCL12 and hypoxia-inducible factor-1alpha expression in carotid arteries as early as 1 day following short-term endoluminal incubation. LPA20:4-induced SPC mobilization and neointima formation were blocked by Ki16425, LPA(1)- and LPA(3)-specific small interfering (si)RNA, and the CXCR4 antagonist POL5551. Ki16425 reduced LPA20:4-mediated neointimal recruitment of SPC as demonstrated by 2-photon microscopy in bone marrow chimeric mice after repopulation with SM22-LacZ transgenic, hematopoietic cells. Moreover, POL5551 decreased the neointimal accumulation of CXCR4(+) SMCs.
  
  
  CONCLUSIONS
  LPA(1) and LPA(3) promote neointima formation through activation of CXCL12-mediated mobilization and recruitment of SPCs.
authors.affiliation: Institute for Molecular Cardiovascular Research, RWTH Aachen University, Pauwelsstr. 30. 52074 Aachen, Germany.
authors.forename: Pallavi
authors.initials: P
authors.lastname: Subramanian
authors.forename: Ela
authors.initials: E
authors.lastname: Karshovska
authors.forename: Patricia
authors.initials: P
authors.lastname: Reinhard
authors.forename: Remco T A
authors.initials: RT
authors.lastname: Megens
authors.forename: Zhe
authors.initials: Z
authors.lastname: Zhou
authors.forename: Shamima
authors.initials: S
authors.lastname: Akhtar
authors.forename: Uwe
authors.initials: U
authors.lastname: Schumann
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Li
authors.forename: Marc
authors.initials: M
authors.lastname: van Zandvoort
authors.forename: Christian
authors.initials: C
authors.lastname: Ludin
authors.forename: Christian
authors.initials: C
authors.lastname: Weber
authors.forename: Andreas
authors.initials: A
authors.lastname: Schober
mesh_terms: D000818:Animals; D017536:Carotid Artery, Common / Q000473:pathology; D002465:Cell Movement / Q000502:physiology*; D054377:Chemokine CXCL12 / Q000502:physiology*; D005260:Female; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000502:physiology*; D049368:Receptors, Lysophosphatidic Acid / Q000502:physiology*; D013234:Stem Cells / Q000166:cytology / Q000502:physiology*; D017539:Tunica Intima / Q000166:cytology / Q000502:physiology*
chemical_list: D054377:Chemokine CXCL12; D049368:Receptors, Lysophosphatidic Acid