Iwakura Atsushi, Luedemann Corinne, Shastry Shubha, Hanley Allison, Kearney Marianne, Aikawa Ryuichi, Isner Jeffrey M, Asahara Takayuki, Losordo Douglas W
Division of Cardiovascular Research, St Elizabeth's Medical Center, Tufts University School of Medicine, Boston, Mass 02135, USA.
Circulation. 2003 Dec 23;108(25):3115-21. doi: 10.1161/01.CIR.0000106906.56972.83. Epub 2003 Dec 15.
We hypothesized that estrogen-induced acceleration of reendothelialization might be mediated in part by effects involving mobilization and incorporation of bone marrow-derived endothelial progenitor cells (EPCs).
Carotid injury was induced in ovariectomized wild-type mice receiving either 17beta-estradiol or placebo. Estradiol treatment significantly accelerated reendothelialization of injured arterial segments within 7 days and resulted in a significant reduction of medial thickness 14 and 21 days after the injury. Significant increases in circulating EPCs 3 days after the injury were observed in the estradiol group compared with placebo-treated mice. These data were further supported by fluorescence-activated cell sorting analysis, which disclosed a significant increase in Sca-1/Flk-1-positive cells in estradiol versus control mice. To evaluate the effects of estradiol on bone marrow-derived EPC incorporation at sites of reendothelialization, carotid injury was established in ovariectomized wild-type mice transplanted with bone marrow from transgenic donors expressing beta-galactosidase transcriptionally regulated by the Tie-2 promoter. Significantly greater numbers of X-gal-positive cells were observed at reendothelialized areas in the estradiol group 3 days after injury as compared with placebo. Fluorescent immunohistochemistry 14 days after the injury documented a marked increase in cells expressing both beta-gal, indicating bone marrow origin and Tie-2 expression, and isolectin B4, also indicating endothelial lineage, in the estradiol group compared with control. In contrast, estradiol did not accelerate reendothelialization or augment EPC mobilization into the peripheral circulation after injury in endothelial nitric oxide synthase-deficient mice (eNOS-/-). Furthermore, estradiol exhibited direct stimulatory effects on EPC mitogenic and migration activity and inhibited EPC apoptosis.
Estradiol accelerates reendothelialization and attenuates medial thickening after carotid injury in part by augmenting mobilization and proliferation of bone marrow-derived EPCs and their incorporation into the recovering endothelium at the site of injury.
我们推测雌激素诱导的再内皮化加速可能部分是由涉及骨髓源性内皮祖细胞（EPCs）动员和整合的效应介导的。
对接受17β - 雌二醇或安慰剂的去卵巢野生型小鼠进行颈动脉损伤。雌二醇治疗在7天内显著加速了损伤动脉段的再内皮化，并在损伤后14天和21天导致中膜厚度显著降低。与接受安慰剂治疗的小鼠相比，雌二醇组在损伤后3天循环EPCs显著增加。荧光激活细胞分选分析进一步支持了这些数据，该分析显示雌二醇处理的小鼠中Sca - 1/Flk - 1阳性细胞显著增加。为了评估雌二醇对骨髓源性EPCs在再内皮化部位整合的影响，对移植了来自表达受Tie - 2启动子转录调控的β - 半乳糖苷酶的转基因供体骨髓的去卵巢野生型小鼠进行颈动脉损伤。与安慰剂相比，损伤后3天在雌二醇组再内皮化区域观察到显著更多的X - 半乳糖苷阳性细胞。损伤后14天的荧光免疫组化显示，与对照组相比，雌二醇组中同时表达β - gal（表明骨髓来源）和Tie - 2表达以及异凝集素B4（也表明内皮谱系）的细胞显著增加。相比之下，在内皮型一氧化氮合酶缺陷小鼠（eNOS - / - ）中，雌二醇在损伤后并未加速再内皮化或增加EPCs向外周循环的动员。此外，雌二醇对EPCs有直接的促有丝分裂和迁移活性作用，并抑制EPCs凋亡。
雌二醇在颈动脉损伤后加速再内皮化并减轻中膜增厚，部分是通过增强骨髓源性EPCs的动员、增殖及其在损伤部位整合到正在恢复的内皮中实现的。
