Aging-induced collateral dysfunction: impaired responsiveness of collaterals and susceptibility to apoptosis via dysfunctional eNOS signaling.
Aging-induced collateral dysfunction: impaired responsiveness of collaterals and susceptibility to apoptosis via dysfunctional eNOS signaling.
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DOI：
10.1007/s12265-011-9280-4
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发表时间：
2011-12
影响因子：
3.4
通讯作者：
Burnett, Mary Susan
中科院分区：
文献类型：
--
作者：
Wang, Jinsong;Peng, XinZhi;Lassance-Soares, Roberta M.;Najafi, Amir H.;Alderman, Lee O.;Sood, Subeena;Xue, Zhenyi;Chan, Rosanna;Faber, James E.;Epstein, Stephen E.;Burnett, Mary Susan
尽管有积极的动物研究，临床血管生成试验一直令人失望，可能是由于存在于人类但通常未在动物中探索的风险因素。我们最近证实了衰老导致受损的侧支重塑和侧支脱落;在这里，我们调查了这些发现的潜在机制。对4个月、10个月和18个月的C57 BL/6 J小鼠进行股动脉结扎;使用激光多普勒灌注成像测量血流。测定小牛肌肉中内皮型一氧化氮合酶（eNOS）和磷酸化eNOS。在分离自年轻和老年小鼠的内皮（EC）和平滑肌（SMC）细胞中评估细胞凋亡。使用基质胶塞测定法测量血管生成。经致死剂量辐照的年轻和老年小鼠接受来自年轻或老年供体的骨髓细胞（BMC），并进行股动脉结扎（FAL）。评估BMC动员和归巢。血流恢复受损，老年小鼠与年轻小鼠相比eNOS和磷酸化eNOS较少（分别为p<0.001和p=0.015）。来自老年小鼠的EC和SMC对凋亡刺激更敏感，但被NO增强药物拯救。在老年小鼠中，血管生成（基质胶塞试验）受损，FAL后BM祖细胞的动员和归巢也受损。虽然动员和归巢改善时，老年小鼠接受BMC移植从年轻的捐助者，血流恢复未能改善。衰老损害BMC动员和归巢，对血管生成刺激的侧支反应，并通过功能失调的eNOS信号传导增加EC和SMC对凋亡的易感性。后者可能导致重塑受损和侧支脱落。这些发现确定了老年患者治疗干预的潜在障碍。
Despite positive animal studies, clinical angiogenesis trials have been disappointing, possibly due to risk factors present in humans but usually unexplored in animals. We recently demonstrated aging causes impaired collateral remodeling and collateral dropout; here, we investigate potential mechanisms responsible for these findings. Four-, 10-, and 18-month-C57BL/6J mice were subjected to femoral artery ligation; flow was measured using laser Doppler perfusion imaging. Endothelial nitric oxide synthase (eNOS) and phosphorylated eNOS were measured in calf muscle. Apoptosis was assessed in endothelial (EC) and smooth muscle (SMC) cells isolated from young and old mice. Angiogenesis was measured using a Matrigel plug assay. Lethally irradiated young and old mice received bone marrow cells (BMC) from either young or old donors and were subjected to femoral artery ligation (FAL). BMC mobilization and homing were assessed. Flow recovery was impaired and less eNOS and phosphorylated eNOS was present in older vs. young mice (p<0.001 and p=0.015, respectively). ECs and SMCs from older mice were more sensitive to an apoptotic stimulus, but were rescued by NO-enhancing drugs. In older mice, angiogenesis (Matrigel plug assay) was impaired, as was mobilization and homing of BM progenitor cells following FAL. Although both mobilization and homing improved when older mice received BMC transplantation from young donors, flow recovery failed to improve. Aging impairs BMC mobilization and homing, collateral responsiveness to angiogenic stimuli, and increases EC and SMC susceptibility to apoptosis via dysfunctional eNOS signaling. The latter could contribute to impaired remodeling and collateral dropout. These finding identify potential obstacles to therapeutic interventions in elderly patients.
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