Institute for Molecular Cardiovascular Research, RWTH Aachen University, Pauwelsstr. 30. 52074 Aachen, Germany.
Circ Res. 2010 Jul 9;107(1):96-105. doi: 10.1161/CIRCRESAHA.109.212647. Epub 2010 Apr 1.
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.
We evaluated the role of LPA receptors in initiating CXCL12-dependent vascular repair by SPCs.
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.
LPA(1) and LPA(3) promote neointima formation through activation of CXCL12-mediated mobilization and recruitment of SPCs.
趋化因子 CXCL12（CXC 基序配体 12）及其受体 CXCR4（CXC 基序受体 4）指导血管损伤后新生内膜中平滑肌祖细胞（SPC）的募集。溶血磷脂酸（LPA）诱导 CXCL12 的产生和未受损动脉中平滑肌细胞（SMC）的新生内膜堆积。因此，我们假设 LPA 可能调节 CXCL12 介导的血管重塑。
我们评估 LPA 受体在 SPC 启动 CXCL12 依赖性血管修复中的作用。
在西方饮食喂养的载脂蛋白 E（-/-）小鼠中进行线诱导颈动脉损伤。通过免疫染色和定量 RT-PCR 研究 LPA 受体表达。在未受损动脉的中膜和损伤诱导的新生内膜中检测到 LPA 受体 LPA（1）和 LPA（3）。伤后一周，LPA（3）mRNA 上调，LPA（1）mRNA 下调。LPA（1/3）拮抗剂 Ki16425 抑制新生内膜形成 71%，同时减少相对新生内膜 SMC 和巨噬细胞含量。此外，Ki16425 抑制新生内膜缺氧诱导因子-1α和 CXCL12 的表达、损伤诱导的外周干细胞抗原-1（Sca-1）（+）/Lin（-）SPC 的动员以及 Sca-1（+）SMC 的新生内膜募集。在野生型小鼠中，LPA20:4 在短时间腔内孵育后仅 1 天即可增加颈动脉中 CXCL12 和缺氧诱导因子-1α的表达。Ki16425、LPA（1）和 LPA（3）特异性 siRNA 以及 CXCR4 拮抗剂 POL5551 阻断 LPA20:4 诱导的 SPC 动员和新生内膜形成。Ki16425 通过骨髓嵌合小鼠的双光子显微镜减少 LPA20:4 介导的 SPC 向新生内膜的募集，这些小鼠在重新植入 SM22-LacZ 转基因造血细胞后。此外，POL5551 减少了 CXCR4（+）SMC 的新生内膜堆积。
LPA（1）和 LPA（3）通过激活 CXCL12 介导的 SPC 动员和募集促进新生内膜形成。
