Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy.
Department of Anatomical, Histological, Forensic and Orthopedic Sciences, Sapienza University of Rome, Rome, Italy.
J Clin Endocrinol Metab. 2019 Jul 1;104(7):2623-2636. doi: 10.1210/jc.2018-02525.
Vascular dysfunction is a common feature in end-organ complications of type 2 diabetes mellitus (T2DM). The endothelium-specific receptor tyrosine kinase Tie2 and its ligand, angiopoietin-1 (Ang1), participate in the processes of vessel repair, renewal, and maturation. However, their dysregulation in T2DM has seldom been investigated.
To examine the relationship between angiogenic Tie2-expressing monocytes (TEMs) and Ang1, and their pharmacological modulation by the phosphodiesterase type 5 inhibitor (PDE5i) sildenafil, in T2DM and in db/db mouse model.
Randomized, double-blind, placebo-controlled study.
db/db male mice were randomly assigned to receive 8 weeks of sildenafil or vehicle. Diabetic men were randomly assigned to receive 4 weeks of sildenafil or placebo.
Peripheral blood cells were investigated by flow cytometry to quantify inflammatory myeloid CD11b+ Gr1+ cells and proangiogenic TEMs in mice and classical CD14++CD16neg monocytes and proangiogenic TEMs in humans at baseline and after treatment. In vitro human tube formation assay was used to test serum angiogenic potential.
We show that TEMs and Ang1 are defective in mouse and human models of diabetes and are normalized by PDE5i treatment. Serum angiogenic properties are impaired in diabetes because they do not support the in vitro formation of capillary-like structures, but they are reestablished by in vivo PDE5i treatment.
Restoring a more physiological Tie2-Ang1 axis with sildenafil reestablishes serum angiogenic properties in diabetes, promoting angiogenic homeostasis.
血管功能障碍是 2 型糖尿病（T2DM）终末器官并发症的常见特征。血管内皮细胞特异性受体酪氨酸激酶 Tie2 及其配体血管生成素-1（Ang1）参与血管修复、更新和成熟的过程。然而，它们在 T2DM 中的失调很少被研究。
研究促血管生成的 Tie2 表达单核细胞（TEMs）与 Ang1 之间的关系，以及磷酸二酯酶 5 抑制剂（PDE5i）西地那非对它们的调节作用，在 T2DM 和 db/db 小鼠模型中。
随机、双盲、安慰剂对照研究。
db/db 雄性小鼠随机分为接受 8 周西地那非或安慰剂治疗。糖尿病男性随机分为接受 4 周西地那非或安慰剂治疗。
通过流式细胞术检测外周血细胞，以在基线和治疗后定量研究小鼠中炎症性髓样 CD11b+Gr1+细胞和促血管生成的 TEMs，以及人类中经典的 CD14++CD16neg 单核细胞和促血管生成的 TEMs。体外人管形成试验用于测试血清的血管生成潜力。
我们表明，TEMs 和 Ang1 在糖尿病的小鼠和人类模型中存在缺陷，并通过 PDE5i 治疗得到纠正。由于不能支持体外毛细血管样结构的形成，糖尿病患者的血清血管生成特性受损，但通过体内 PDE5i 治疗可得到恢复。
用西地那非恢复更生理性的 Tie2-Ang1 轴可恢复糖尿病患者的血清血管生成特性，促进血管生成的稳态。
