衰老血管内皮损伤修复的细胞来源

“Man is as old as his arteries.” The outcomes of the aging-related modifications are the impairment of homeostasis of the irrigated organs and resultant target organ damage. The endothelial cell plays critical roles in the regulation of vascular functions, and therefore the endothelial cell senescence has severe impact on vascular ageing and related diseases. In the present study, using vascular endothelial ageing model, myocardial infarction，hindlimb ischemia，atherosclerosis, lineage tracing and double homologous recombination，we could explore the cellular origin of angiogenesis during vascular repair in ageing vessels. To establish vascular endothelial ageing model, P21 and P16 are overexpressed in vascular endothelial cells and the proliferation of endothelial cells is repressed by using transgenic mice. By hybridizing of fibroblast, pericyte, stem cell, endothelial progenitor cell, immunocyte, macrophage specific transgenic mice and vascular endothelial ageing mice and double combination reporter mice, we could trace vascular endothelial cells and non-vascular endothelial cells simultaneously, track the fate of the cell lineages that could differentiate and transdifferentiate into vascular endothelial cells, and identify the cell type contributing to angiogenesis during repair. This study would provide novel and valuable information for revascularization of vascular ageing.

“人老如其动脉”。在与衰老相关的所有疾病中，心血管疾病仍是老年人发病率和死亡率的首要原因。内皮细胞在血管功能调节中起关键作用，所以内皮细胞衰老会对血管衰老和血管疾病产生严重的影响。本项目结合小鼠血管内皮衰老模型，心肌梗死、下肢缺血和动脉粥样硬化损伤模型，以及双重同源重组系统，利用遗传谱系示踪技术探索衰老血管内皮细胞在损伤修复过程中新生血管内皮的细胞来源。利用转基因小鼠在血管内皮细胞中过表达P21和P16，抑制内皮细胞增殖，建立血管内皮衰老模型。将成纤维细胞、血管周细胞、干细胞、内皮祖细胞、免疫细胞和巨噬细胞遗传示踪小鼠，分别与内皮细胞衰老模型小鼠和双重同源重组报告基因小鼠杂交，同时谱系示踪血管内皮细胞和非血管内皮细胞，全面追踪可能分化或转分化成血管内皮细胞的细胞谱系的命运，明确参与衰老血管内皮修复的细胞类型，为衰老血管再生研究提供新的有参考价值的信息。

“人老如其动脉”。在与衰老相关的所有疾病中，心血管疾病仍是老年人发病率和死亡率的首要原因。内皮细胞在血管功能调节中起关键作用，所以内皮细胞衰老会对血管衰老和血管疾病产生严重的影响。本项目利用遗传谱系示踪技术探索血管内皮在损伤修复过程中新生血管内皮的细胞来源。利用转基因小鼠在血管内皮细胞中过表达P21，抑制内皮细胞增殖，建立血管内皮衰老模型。遗传谱系示踪与脉冲追踪标记策略表明，心血管损伤修复过程中几乎所有新的冠状血管都是来源于预先存在的内皮细胞，而非其它细胞谱系。这些数据表明，诱导新生血管的治疗策略不应以其它细胞系转分化为靶点。相反，先前存在的内皮细胞更可能成为促进损伤后新生血管和驱动心脏再生的治疗靶点。