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

Abstract

Rationale : 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. Objectives : We evaluated the role of LPA receptors in initiating CXCL12-dependent vascular repair by SPCs. Methods and 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-1α 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-1α 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.