Department of Cardiology and Pulmonary Medicine, Georg August University of Goettingen, Germany.
Cardiovasc Res. 2012 Jan 1;93(1):170-80. doi: 10.1093/cvr/cvr275. Epub 2011 Nov 6.
Bone marrow (BM) progenitors participate in new vessel formation and endothelial repair. The leptin receptor (ObR) is expressed on hematopoietic cells; however, the effects of leptin on BM progenitor cells and their angiogenic potential are unknown.
In the present study, we show that the short-term administration of leptin (over five consecutive days) into wild-type mice increased the number of circulating, BM-derived sca-1(+), flk-1(+) vascular progenitors, 95 ± 1.7% of which also expressed ObR. Ex vivo stimulation of BM cells with leptin enhanced the expression of NADPH oxidase isoform 2 (NOX2), and the leptin-induced increase in reactive oxygen species production, matrix metalloproteinase-9 (MMP9) expression and circulating soluble KitL levels was absent in mice lacking NOX2. Furthermore, intraperitoneal injections of leptin improved perfusion and increased the number of BM-derived, CD31-positive endothelial cells in ischaemic hindlimbs after femoral artery ligation. The effects of leptin on the mobilization of sca-1(+), flk-1(+) cells and neovascularization were abolished in mice transplanted with BM from ObR-deficient and in NOX2(-/-) mice.
Our findings suggest that the angiogenic effects of leptin involve sca-1(+), flk-1(+) vascular progenitor cells mobilized from the BM in response to ObR-mediated activation of NOX2, increased MMP9 expression, and sKitL release.
骨髓（BM）祖细胞参与新血管形成和内皮修复。瘦素受体（ObR）在造血细胞上表达；然而，瘦素对 BM 祖细胞及其血管生成潜能的影响尚不清楚。
在本研究中，我们表明，瘦素（连续五天）的短期给药增加了循环中的、BM 来源的 sca-1(+)、flk-1(+)血管祖细胞的数量，其中 95±1.7%也表达 ObR。瘦素对 BM 细胞的体外刺激增强了 NADPH 氧化酶同工型 2（NOX2）的表达，并且瘦素诱导的活性氧物质产生、基质金属蛋白酶-9（MMP9）表达和循环可溶性 KitL 水平的增加在缺乏 NOX2 的小鼠中不存在。此外，瘦素的腹腔内注射改善了灌注，并增加了股动脉结扎后缺血后肢中 BM 来源的、CD31 阳性的内皮细胞的数量。ObR 缺陷小鼠和 NOX2(-/-)小鼠的 BM 移植消除了瘦素对 sca-1(+)、flk-1(+)细胞动员和新生血管形成的作用。
我们的研究结果表明，瘦素的血管生成作用涉及到 ObR 介导的 NOX2 激活后从 BM 动员的 sca-1(+)、flk-1(+)血管祖细胞，增加 MMP9 表达和 sKitL 释放。
