Piqueras Laura, Reynolds Andrew R, Hodivala-Dilke Kairbaan M, Alfranca Arántzazu, Redondo Juan M, Hatae Toshihisa, Tanabe Tadashi, Warner Timothy D, Bishop-Bailey David
Cardiac, Vascular & Inflammation Research, William Harvey Research Institute, Barts and the London, Queen Mary University London, Charterhouse Sq, London EC1M 6BQ, UK.
Arterioscler Thromb Vasc Biol. 2007 Jan;27(1):63-9. doi: 10.1161/01.ATV.0000250972.83623.61. Epub 2006 Oct 26.
The role of the nuclear receptor peroxisome-proliferator activated receptor (PPAR)-beta/delta in endothelial cells remains unclear. Interestingly, the selective PPARbeta/delta ligand GW501516 is in phase II clinical trials for dyslipidemia. Here, using GW501516, we have assessed the involvement of PPARbeta/delta in endothelial cell proliferation and angiogenesis.
Western blot analysis indicated PPARbeta/delta was expressed in primary human umbilical and aortic endothelial cells, and in the endothelial cell line, EAHy926. Treatment with GW501516 increased human endothelial cell proliferation and morphogenesis in cultures in vitro, endothelial cell outgrowth from murine aortic vessels in vitro, and angiogenesis in a murine matrigel plug assay in vivo. GW501516 induced vascular endothelial cell growth factor mRNA and peptide release, as well as adipose differentiation-related protein (ADRP), a PPARbeta/delta target gene. GW501516-induced proliferation, morphogenesis, vascular endothelial growth factor (VEGF), and ADRP were absent in endothelial cells transfected with dominant-negative PPARbeta/delta. Furthermore, treatment of cells with cyclo-VEGFI, a VEGF receptor1/2 antagonist, abolished GW501516-induced endothelial cell proliferation and tube formation.
PPARbeta/delta is a novel regulator of endothelial cell proliferation and angiogenesis through VEGF. The use of GW501516 to treat dyslipidemia may need to be carefully monitored in patients susceptible to angiogenic disorders.
核受体过氧化物酶体增殖物激活受体（PPAR）-β/δ在内皮细胞中的作用尚不清楚。有趣的是，选择性PPARβ/δ配体GW501516正处于血脂异常的II期临床试验中。在此，我们使用GW501516评估了PPARβ/δ在内皮细胞增殖和血管生成中的作用。
蛋白质印迹分析表明，PPARβ/δ在原代人脐动脉内皮细胞、主动脉内皮细胞以及内皮细胞系EAHy926中均有表达。用GW501516处理可增加体外培养的人内皮细胞增殖和形态发生、体外小鼠主动脉血管的内皮细胞生长以及体内小鼠基质胶栓试验中的血管生成。GW501516可诱导血管内皮细胞生长因子mRNA和肽的释放，以及PPARβ/δ靶基因脂肪分化相关蛋白（ADRP）。在转染了显性负性PPARβ/δ的内皮细胞中，GW501516诱导的增殖、形态发生、血管内皮生长因子（VEGF）和ADRP均缺失。此外，用VEGF受体1/2拮抗剂环VEGFI处理细胞可消除GW501516诱导的内皮细胞增殖和管形成。
PPARβ/δ是通过VEGF调节内皮细胞增殖和血管生成的新型调节因子。在易患血管生成性疾病的患者中，使用GW501516治疗血脂异常可能需要仔细监测。
