Centre for Research in Vascular Biology, BioSciences Institute, University College Cork, Cork, Ireland.
Atherosclerosis. 2011 May;216(1):74-82. doi: 10.1016/j.atherosclerosis.2011.01.037. Epub 2011 Feb 2.
We examined the role of C-fms+ cells in response to vascular injury with a focus on the temporal and spatial platelet interactions, monocyte survival and proliferation within the evolving neointimal lesion and monocyte proliferation within the circulation and specified monocyte reservoir sites. Finally, we investigated the therapeutic effect of C-fms kinase inhibition (CFKI) on neointimal hyperplasia post vessel injury.
We utilized murine carotid-wire injury, a transgenic C-fms reporting mouse model, confocal microscopy, shear-flow studies, specific C-fms signalling inhibition to determine the activation, mobilization and recruitment of C-fms+ monocytes in the context of early and late vessel remodelling. C-fms+ cells were recruited as early as 4h and accumulated over time in the neointima following injury. Monocyte interaction with platelet thrombus under flow and in vivo, in addition to monocyte mobilisation into the circulation post-injury was impaired by CFKI administration. Sustained inhibition of C-fms over 1-2 weeks abrogated the neointimal response but preserved re-endothelialisation post-injury.
These data establish C-fms as a key regulator of the vascular response to injury and a potentially attractive therapeutic target in disease states where neointimal hyperplasia, monocyte activation and pathologic remodelling are prominent and endothelial homeostasis is desirable.
我们研究了 C-fms+细胞在血管损伤反应中的作用，重点关注血小板在不断发展的新生内膜病变中的时空相互作用、单核细胞的存活和增殖，以及循环中和特定单核细胞库位中的单核细胞增殖。最后，我们研究了 C-fms 激酶抑制 (CFKI) 对血管损伤后新生内膜增生的治疗效果。
我们利用了小鼠颈动脉线损伤、一种转基因 C-fms 报告小鼠模型、共聚焦显微镜、切变流研究和特定的 C-fms 信号抑制，以确定 C-fms+单核细胞在早期和晚期血管重塑中的激活、动员和募集。在损伤后，C-fms+细胞在 4 小时内被招募，并随着时间的推移在新生内膜中积累。CFKI 给药可损伤后单核细胞与血小板血栓在流动中和体内的相互作用以及单核细胞向循环中的动员。持续抑制 C-fms 1-2 周可消除新生内膜反应，但可保留损伤后的再内皮化。
这些数据确立了 C-fms 作为血管对损伤反应的关键调节因子，以及在新生内膜增生、单核细胞激活和病理性重塑突出且需要内皮稳态的疾病状态下具有吸引力的治疗靶点。
