Department of Pathology, University of Washington, Seattle, 98109, USA.
Arterioscler Thromb Vasc Biol. 2012 Apr;32(4):955-61. doi: 10.1161/ATVBAHA.111.241034. Epub 2012 Feb 2.
The objective of this study was to define a role for sphingosine-1-phosphate receptor 3 (S1PR3) in intimal hyperplasia.
A denudation model of the iliac-femoral artery in wild-type and S1PR3-null mice was used to define a role for S1PR3 in the arterial injury response because we found in humans and mice that expression of S1PR3 was higher in these arteries compared with carotid arteries. At 28 days after surgery, wild-type arteries formed significantly larger lesions than S1PR3-null arteries. Bromodeoxyuridine labeling experiments demonstrated that on injury, wild-type arteries exhibited higher medial as well as intimal proliferation than S1PR3-null arteries. Because S1PR3 expression in vitro was low, we expressed S1PR3 in S1PR3-null smooth muscle cells (SMCs) using retroviral-mediated gene transfer to study the effects of S1PR3 on cell functions and signaling. SMCs expressing S1PR3, but not vector-transfected controls, responded to sphingosine-1-phosphate stimulation with activation of Rac, Erk, and Akt. SMCs expressing S1PR3 also migrated more.
In humans and mice, S1PR3 expression was higher in iliac-femoral arteries compared with carotid arteries. S1PR3 promoted neointimal hyperplasia on denudation of iliac-femoral arteries in mice, likely by stimulating cell migration and proliferation through activation of signaling pathways involving Erk, Akt, and Rac.
本研究旨在确定鞘氨醇-1-磷酸受体 3（S1PR3）在血管内膜增生中的作用。
本研究采用股动脉-髂动脉剥脱模型，以明确 S1PR3 在动脉损伤反应中的作用，因为我们在人类和小鼠中发现，与颈动脉相比，S1PR3 在这些动脉中的表达更高。术后 28 天，野生型动脉形成的病变明显大于 S1PR3 敲除型动脉。溴脱氧尿苷标记实验表明，在损伤后，野生型动脉的中膜和内膜增生均高于 S1PR3 敲除型动脉。由于 S1PR3 在体外的表达水平较低，我们通过逆转录病毒介导的基因转移在 S1PR3 敲除型平滑肌细胞（SMC）中表达 S1PR3，以研究 S1PR3 对细胞功能和信号转导的影响。表达 S1PR3 的 SMC 而非载体转染对照，对鞘氨醇-1-磷酸刺激表现出 Rac、Erk 和 Akt 的激活。表达 S1PR3 的 SMC 迁移能力也更强。
在人类和小鼠中，S1PR3 在股动脉-髂动脉中的表达高于颈动脉。S1PR3 通过激活涉及 Erk、Akt 和 Rac 的信号通路，刺激细胞迁移和增殖，促进小鼠股动脉-髂动脉剥脱后的新生内膜增生。
