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背景:沙利度胺治疗胃肠道血管畸形所致的难治性消化道出血安全、有效,而胃肠道血管畸形所致的消化道出血可能与缺氧引起的血管代偿性增生有关。目的:探讨人脐静脉内皮细胞(HUVEC)血管生成素2(Ang-2)、Notch1、Dll4和缺氧诱导因子(HIF)-1α在缺氧环境中的表达以及沙利度胺的干预机制。方法:HUVEC分别于常氧和缺氧环境下培养。缺氧培养的HUVEC分为溶剂对照组和不同浓度(25、50、100、200μg/mL)沙利度胺组。以Real-time PCR和蛋白质印迹法分别检测Ang-2、Notch1、Dll4、HIF-1αmRNA和蛋白表达。结果:缺氧条件下Ang-2、Notch1、Dll4、HIF-1αmRNA和蛋白表达均高于常氧状态,差异有统计学意义(P<0.05)。沙利度胺可呈浓度依赖性地抑制HUVEC Ang-2、Notch1、Dll4 mRNA和蛋白表达(P<0.05)。结论:沙利度胺对Ang-2、Notch1、Dll4表达的抑制作用可能是其抑制血管生成从而治疗胃肠道血管畸形致消化道出血的机制之一。
BACKGROUND: Thalidomide is safe and effective in the treatment of refractory gastrointestinal bleeding caused by vascular malformation in the gastrointestinal tract. Gastrointestinal hemorrhage caused by vascular malformation may be related to vascular compensatory hyperplasia induced by hypoxia. AIM: To investigate the expression of Ang-2, Notch1, Dll4 and hypoxia inducible factor (HIF) -1α in hypoxic environment in human umbilical vein endothelial cells (HUVECs) and the mechanism of thalidomide intervention. Methods: HUVECs were cultured under normoxia and hypoxia respectively. HUVEC cultured in hypoxia were divided into solvent control group and thalidomide group with different concentration (25, 50, 100, 200μg / mL). The mRNA and protein expressions of Ang-2, Notch1, Dll4 and HIF-1α were detected by Real-time PCR and Western blot respectively. Results: The mRNA and protein expressions of Ang-2, Notch1, Dll4 and HIF-1α in hypoxia were significantly higher than those in normoxia (P <0.05). Thalidomide inhibited the mRNA and protein expression of Ang-2, Notch1 and Dll4 in HUVEC in a concentration-dependent manner (P <0.05). Conclusion: The inhibitory effect of thalidomide on the expression of Ang-2, Notch1 and Dll4 may be one of the mechanisms of its inhibition of angiogenesis and treatment of gastrointestinal hemorrhage caused by gastrointestinal malformations.