Lysophosphatidic Acid Receptors LPA1 and LPA3 Promote CXCL12-Mediated Smooth Muscle Progenitor Cell Recruitment in Neointima Formation
Lysophosphatidic Acid Receptors LPA1 and LPA3 Promote CXCL12-Mediated Smooth Muscle Progenitor Cell Recruitment in Neointima Formation
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DOI：
10.1161/circresaha.109.212647
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发表时间：
2010-07-09
影响因子：
20.1
通讯作者：
Schober, Andreas
中科院分区：
文献类型：
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作者：
Subramanian, Pallavi;Karshovska, Ela;Schober, Andreas
原理：趋化因子CXCL12 （CXC基序配体12）及其受体cxcr4 （CXC基序受体4）在血管损伤后新生内膜形成过程中指导平滑肌祖细胞（SPCs）的募集。溶血磷脂酸（LPA）在未损伤动脉中诱导CXCL12和平滑肌细胞（SMCs）的新内膜积累。因此，我们假设LPA可能调节cxcl12介导的血管重构。目的：我们评估LPA受体在SPCs启动cxcl12依赖性血管修复中的作用。方法与结果：采用钢丝致颈动脉损伤的方法，用western-type日粮治疗载脂蛋白E-/-小鼠。采用免疫染色和定量RT-PCR检测LPA受体的表达。LPA受体LPA(1)和LPA(3)分别存在于未损伤动脉和损伤新生内膜中。损伤后1周，LPA(3) mRNA表达上调，LPA(1) mRNA表达下调。LPA（1/3）拮抗剂Ki16425抑制新生内膜形成71%，降低新生内膜相对SMCs和巨噬细胞含量。此外，Ki16425还能抑制新生内膜缺氧诱导因子-1 α和CXCL12的表达、损伤诱导的外周干细胞抗原-1(ca-1)(+)/Lin(-) SPC的动员以及ca-1(+)SMCs的新生内膜募集。在野生型小鼠中，LPA20:4早在短期腔内孵育后1天就增加了颈动脉中CXCL12和缺氧诱导因子-1 α的表达。lpa20:4诱导的SPC动员和新内膜形成被Ki16425、LPA(1)-和LPA(3)-特异性小干扰（si） RNA和CXCR4拮抗剂POL5551阻断。通过双光子显微镜观察，在SM22-LacZ转基因造血细胞再生后的骨髓嵌合小鼠中，Ki16425降低了LPA20: 4介导的SPC新内膜募集。此外，POL5551降低了CXCR4(+) SMCs的内膜积累。结论：LPA(1)和LPA(3)通过激活cxcl12介导的SPCs的动员和募集来促进新内膜的形成。（Circ Res. 2010; 107: 96-105）
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-1 alpha 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-1 alpha 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. (Circ Res. 2010; 107: 96-105.)