GI Division, Shanghai Jiao-Tong University School of Medicine Renji Hospital, Shanghai Institution of Digestive Disease, Key Laboratory of Gastroenterology & Hepatology, Ministry of Health (Shanghai Jiao-Tong University), and State Key Laboratory of Oncogene and Related Genes, Shanghai, China.
J Gastroenterol Hepatol. 2012 Jun;27(6):1094-101. doi: 10.1111/j.1440-1746.2011.06967.x.
The pathogenesis of angiodysplasia is still not fully understood and effective therapy is not available. Thalidomide was reported to be effective in the treatment of angiodysplasia, but the mechanisms underlying its activity are, as yet, unknown. We aimed to investigate the expression of vascular endothelial growth factor (VEGF) in angiodysplasia tissues, and the role of hypoxia-inducible factor-1α (HIF-1α) and basic fibroblast growth factor (bFGF) on VEGF expression in human umbilical vein endothelial cells (HUVEC). Additionally, we aimed to study the role of thalidomide in these parameters.
Immunohistochemistry was performed to visualize VEGF in angiodysplasia lesions. HUVEC were incubated under hypoxic conditions or in the presence of bFGF. Effects of exposure to thalidomide were studied. Cell growth was assessed in methylthiazolyte-trazolium assays. Enzyme-linked immunosorbent assays and real-time polymerase chain reaction were performed to assess the expression of VEGF at protein and mRNA levels. Western blot was performed to detect the expression of HIF-1α under hypoxic conditions.
VEGF was strongly expressed in 75% of patients with angiodysplasia lesions, as compared to expression in patients without angiodysplasia lesions. VEGF was also induced in HUVEC under hypoxic conditions (P < 0.05). bFGF was found to stimulate the proliferation of HUVEC and enhance the expression of VEGF. Thalidomide suppressed bFGF-induced proliferation significantly and decreased VEGF expression, both at the protein and mRNA levels. Thalidomide also inhibited HIF-1α in a dose-dependent manner (P < 0.05).
VEGF may play an important role in the pathogenesis of angiodysplasia. Thalidomide can suppress VEGF, either induced by HIF-1α or bFGF.
血管发育不良的发病机制尚不完全清楚，也没有有效的治疗方法。沙利度胺已被报道对血管发育不良有效，但它的作用机制尚不清楚。本研究旨在探讨血管内皮生长因子（VEGF）在血管发育不良组织中的表达，以及低氧诱导因子-1α（HIF-1α）和碱性成纤维细胞生长因子（bFGF）对人脐静脉内皮细胞（HUVEC）中 VEGF 表达的作用。此外，我们还研究了沙利度胺在这些参数中的作用。
采用免疫组化法检测血管发育不良病变中 VEGF 的表达。在缺氧条件下或 bFGF 存在的情况下孵育 HUVEC。研究沙利度胺的作用。通过噻唑蓝比色法评估细胞生长。通过酶联免疫吸附试验和实时聚合酶链反应检测 VEGF 在蛋白和 mRNA 水平的表达。采用 Western blot 检测缺氧条件下 HIF-1α的表达。
与无血管发育不良病变的患者相比，75%的血管发育不良病变患者 VEGF 表达强烈。在缺氧条件下，HUVEC 中也诱导了 VEGF 的表达（P<0.05）。bFGF 被发现可刺激 HUVEC 的增殖，并增强 VEGF 的表达。沙利度胺显著抑制 bFGF 诱导的增殖，并降低 VEGF 的表达，无论是在蛋白水平还是在 mRNA 水平。沙利度胺还呈剂量依赖性抑制 HIF-1α（P<0.05）。
VEGF 可能在血管发育不良的发病机制中起重要作用。沙利度胺可以抑制由 HIF-1α或 bFGF 诱导的 VEGF。
