Department of Endocrinology, Wuhan General Hospital of Guangzhou Command, Wuhan, Hubei, China.
Department of Hematology and Medical Oncology, School of Medicine, Emory University, Atlanta, GA.
Diabetes. 2018 Oct;67(10):2084-2095. doi: 10.2337/db17-1583. Epub 2018 Jul 19.
Growth differentiation factor 11 (GDF11) has been shown to promote stem cell activity and rejuvenate the function of multiple organs in old mice, but little is known about the functions of GDF11 in the diabetic rat model of hindlimb ischemia. In this study, we found that systematic replenishment of GDF11 rescues angiogenic function of endothelial progenitor cells (EPCs) and subsequently improves vascularization and increases blood flow in diabetic rats with hindlimb ischemia. Conversely, anti-GDF11 monoclonal antibody treatment caused impairment of vascularization and thus, decreased blood flow. In vitro treatment of EPCs with recombinant GDF11 attenuated EPC dysfunction and apoptosis. Mechanistically, the GDF11-mediated positive effects could be attributed to the activation of the transforming growth factor-β/Smad2/3 and protein kinase B/hypoxia-inducible factor 1α pathways. These findings suggest that GDF11 repletion may enhance EPC resistance to diabetes-induced damage, improve angiogenesis, and thus, increase blood flow. This benefit of GDF11 may lead to a new therapeutic approach for diabetic hindlimb ischemia.
生长分化因子 11（GDF11）已被证明可促进干细胞活性并使老年小鼠的多个器官功能恢复年轻，但对于 GDF11 在糖尿病大鼠后肢缺血模型中的功能知之甚少。在这项研究中，我们发现系统补充 GDF11 可挽救内皮祖细胞（EPC）的血管生成功能，随后可改善血管生成并增加糖尿病大鼠后肢缺血的血流量。相反，抗 GDF11 单克隆抗体治疗会损害血管生成，从而降低血流量。体外用重组 GDF11 处理 EPC 可减轻 EPC 功能障碍和细胞凋亡。从机制上讲，GDF11 介导的积极作用可归因于转化生长因子-β/Smad2/3 和蛋白激酶 B/缺氧诱导因子 1α 通路的激活。这些发现表明，GDF11 的补充可能增强 EPC 对糖尿病引起的损伤的抵抗力，改善血管生成，从而增加血流量。GDF11 的这种益处可能为糖尿病性后肢缺血提供一种新的治疗方法。
