Synergistic targeting with bone marrow-derived cells and PDGF improves diabetic vascular function.
Synergistic targeting with bone marrow-derived cells and PDGF improves diabetic vascular function.
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骨髓源性细胞和 PDGF 的协同靶向可改善糖尿病血管功能。
DOI：
10.1152/ajpheart.00652.2005
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发表时间：
2006
期刊：
影响因子：
--
通讯作者：
Edelberg,JayM
中科院分区：
文献类型：
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作者：
Klibansky,DavidA;Chin,Andrew;Duignan,IngaJ;Edelberg,JayM
糖尿病与血管疾病的风险增加有关，全身内皮祖细胞（EPCs）和周围血管功能显著改变。为了确定不同的血管室在糖尿病血管化损伤中的作用，我们在一个等基因的胸廓同种异体心脏移植模型中使用链脲佐菌素和对照组治疗的3岁C57Bl/6小鼠，发现移植到糖尿病小鼠体内的野生型心脏组织血管化明显延迟。为了研究这种损伤的基础，我们将从糖尿病小鼠和对照小鼠中分离的骨髓细胞移植到完整的、未辐照的18岁C57Bl/6小鼠中，检测糖尿病骨髓细胞的功能。C57Bl/6小鼠的EPCs和外周内皮细胞功能均受损。重要的是，来自对照组而非糖尿病患者骨髓的细胞整合到移植的同种异体心脏移植物中。为了评估糖尿病对局部血管变化的贡献，糖尿病小鼠被注射血小板衍生生长因子(PDGF)-AB，促进野生型小鼠的心脏血管生成。然而，PDGF-AB增强了对照小鼠的同种异体移植功能，而PDGF-AB治疗的糖尿病小鼠的心脏移植活性明显降低。为了解释全身骨髓来源细胞与局部血管通路之间的潜在相互作用，我们将糖尿病小鼠移植给野生型骨髓细胞，并在PDGF-AB的胸壁进行预处理，结果表明，只有在联合治疗组，同种异体移植物功能和供体细胞募集得到改善。总之，这些研究表明糖尿病对心脏血管生成的损害可以通过靶向局部营养通路和全身细胞功能之间的协同作用来逆转。
Diabetes mellitus is associated with an increased risk of vascular disease, with significant alterations in systemic endothelial progenitor cells (EPCs) and peripheral vascular function. To identify the contribution of the different vascular compartments in the diabetic impairment of vascularization, we employed streptozotocin- and control-treated 3-mo-old C57Bl/6 mice in an isogeneic pinnal cardiac allograft model, revealing a significant delay in vascularization of wild-type cardiac tissue transplanted into diabetic mice. To investigate the basis of this impairment, the function of diabetic bone marrow cells was tested by transplantation of bone marrow cells isolated from diabetic and control mice into intact, unirradiated 18-mo-old C57Bl/6 mice, which have impaired function of both EPCs and peripheral endothelial cells. Importantly, cells derived from control, but not diabetic, bone marrow integrated into transplanted cardiac allografts. To assess the contribution of diabetic changes in the local vasculature, diabetic mice were treated with pinnal injections of platelet-derived growth factor (PDGF)-AB, which promotes cardiac angiogenesis in wild-type mice. However, whereas PDGF-AB enhanced allograft function in control mice, the activity of the cardiac transplants in the PDGF-AB-treated diabetic mice was significantly decreased. To decipher the potential interactions between systemic bone marrow-derived cells and local vascular pathways, diabetic mice were transplanted with wild-type bone marrow cells with or without PDGF-AB pinnal pretreatment, resulting in improved allograft function and donor cell recruitment only in the combination treatment arm. Overall, these studies show that the diabetic impairment in cardiac angiogenesis can be reversed by targeting the synergism between local trophic pathways and systemic cell function.