Haeme oxygenase promotes progenitor cell mobilization, neovascularization, and functional recovery after critical hindlimb ischaemia in mice
Haeme oxygenase promotes progenitor cell mobilization, neovascularization, and functional recovery after critical hindlimb ischaemia in mice
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DOI：
10.1093/cvr/cvm107
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发表时间：
2008-05-01
影响因子：
10.8
通讯作者：
Wollert, Kai C.
中科院分区：
文献类型：
--
作者：
Tongers, Joern;Knapp, Julia-Marie;Wollert, Kai C.
目的：血管新生是慢性脑缺血长期功能恢复的重要因素。我们推测，血红素加氧酶（HO）是必要的祖细胞招聘，新生血管，和血流恢复后，关键后肢缺血（HLI）。方法和结果股动脉结扎FVB/N小鼠近端的浅，深分支。通过激光多普勒灌注成像测定缺血后肢的血流量。通过同工凝集素染色测量毛细血管密度，并通过FACS分析测定Sca-1（+）/Kdr（+）祖细胞的动员。在Tie 2-lacZ转基因骨髓移植后评估祖细胞向缺血后肢的募集。在接受HO抑制剂锡原卟啉-IX（25 mg/kg腹腔注射，每隔一天）。HO抑制小鼠出现更明显的肢体坏死，与后肢运动功能受损相关。HO抑制后缺血后肢毛细血管密度和Sca-1（+）/Kdr（+）祖细胞动员显著降低。将Tie 2-lacZ转基因骨髓细胞移植到致死剂量照射的野生型小鼠后，在HO抑制小鼠的缺血后肢肌肉中检测到较少的LacZ（+）细胞。机械，HO抑制防止建立一个基质细胞衍生因子-1梯度缺血后肢和骨髓之间的祖细胞动员。结论HO是需要祖细胞招募，新生血管，和功能恢复后HLI。
Aims Neovascularization is an important element of tong-term functional recovery during chronic ischaemia. We postulated that haeme oxygenase (HO) is required for progenitor cell recruitment, neovascularization, and blood flow recovery after critical hindlimb ischaemia (HLI).Methods and results The femoral artery was ligated in FVB/N mice proximal to its superficial and deep branches. Blood flow in the ischaemic hindlimb was determined by Laser Doppler perfusion imaging. Capillary density was measured by isolectin staining, and mobilization of Sca-1(+)/Kdr(+) progenitor cells by FACS analysis. Progenitor cell recruitment to the ischaemic hindlimb was assessed after Tie2-lacZ transgenic bone marrow transplantation. Blood flow recovery after femoral artery ligation was significantly blunted in mice treated with the HO inhibitor tin protoporphyrin-IX (25 mg/kg i.p., every other day). HO-inhibited mice developed more pronounced Limb necrosis, associated with impaired hindlimb motor function. Capillary density in the ischaemic hindlimb and mobilization of Sca-1(+)/Kdr(+) progenitor cells were significantly reduced after HO inhibition. After transplantation of Tie2-lacZ transgenic bone marrow cells into lethally irradiated wild-type mice, fewer LacZ(+) cells were detected in the ischaemic hindlimb muscle of HO-inhibited mice. Mechanistically, HO inhibition prevented the establishment of a stromal cell-derived factor-1 gradient for progenitor cell mobilization between the ischaemic hindlimb and bone marrow.Conclusion HOs are required for progenitor cell recruitment, neovascularization, and functional recovery after HLI.