Roles of angiogenic factors and endothelin-I in gastric ulcer healing
Roles of angiogenic factors and endothelin-I in gastric ulcer healing
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DOI：
10.1042/cs103s450s
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发表时间：
2002-08-01
期刊：
影响因子：
6
通讯作者：
Yamashita, K
中科院分区：
文献类型：
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作者：
Akimoto, M;Hashimoto, H;Yamashita, K
内皮素（Endothelins，ET）通过ET受体直接或间接参与血管生成。在胎儿早期血管生成过程中，血管内皮生长因子（VEGF）及其受体激酶插入结构域受体（KDR）和fms样酪氨酸激酶-1（Flt-1）是全身血管系统发育所必需的。在晚期血管生成中，基质细胞衍生因子（SDF-1）及其受体CXC趋化因子受体4（CXCR 4）以器官特异性方式起作用，以促进供应胃肠道的大血管的形成和发育。我们研究了这些配体受体在胃溃疡愈合过程中血管生成中的作用。我们研究了以下五组，每组包括10例内镜确诊的胃溃疡：活动期（GA），愈合期（GH）和瘢痕期（GS）的胃溃疡位于角;幽门螺杆菌（Hp）阳性胃炎（gast+）;和Hp阴性胃炎（gast-）。溃疡组全部Hp阳性。研究材料包括房角病变的冷冻活检标本。酶免疫法测定ET-1。其他因子用逆转录-PCR法检测。酶免疫法检测胃粘膜内皮素1（ET-1）、内皮素受体（ETAR）、基质细胞衍生因子1（SDF-1）和趋化因子受体4（CXCR 4）的表达。ET-1和ETAR在GH期达高峰（ET：P < 0.05，ETAR：P < 0.01）。VEGF mRNA在GA期间略有增加，但各组之间无显著差异。GA期KDR和Flt-1水平较高，显著高于GH和GS期（P < 0.05）。与GA相比，GH和GS处理的SDF-1水平显著降低（P <0.01），CXCR 4水平显著升高（P < 0.01）。免疫组化结果显示，GH和GS时内皮细胞、血管平滑肌和胃上皮细胞中均可见ET-I和ETAR阳性细胞，内皮细胞和胃上皮细胞中可见CXCR 4阳性细胞。我们的研究结果表明，VEGF受体主要在溃疡发展的早期表达，并参与血管生成的初始阶段。SDF-1受体和ETAR主要在GH和GS期间表达，并在晚期血管生成期间参与血管成熟和胃粘膜再生。
Endothelins (ETs) participate directly and indirectly in angiogenesis via ET receptors. During early fetal angiogenesis, vascular endothelial growth factor (VEGF) and its receptors kinase insert domain-containing receptor (KDR) and fms-like tyrosine kinase-1 (Flt-1) are required for the development of the systemic vasculature. In late angiogenesis, stromal-cell-derived factor (SDF-1) and its receptor CXC chemokine receptor 4 (CXCR4) act in an organ-specific manner to promote the formation and development of large blood vessels supplying the gastrointestinal tract. We studied the roles of these ligand receptors in angiogenesis during healing of gastric ulcers. We studied the following five groups, each consisting of ten cases of endoscopically confirmed gastric ulcer: active stage (GA), healing stage (GH) and scar stage (GS) of gastric ulcers located in the angulus; Helicobacter pylori (Hp)-positive gastritis (gast+); and Hp-negative gastritis (gast-). All cases in the ulcer groups were Hp-positive. The study materials consisted of frozen biopsy specimens of lesions arising in the angulus. ET-1 was measured by enzyme immunoassay. The other factors were assayed by reverse-transcription-PCR. The distributions of ET-1, ETA receptor (ETAR), SDF-1 and CXCR4 in the gastric mucosa were evaluated by enzyme immunoassay. ET-I and ETAR reached peak levels during the GH (ET: P < 0.05, ETAR: P < 0.01). VEGF mRNA increased slightly during the GA, but did not differ significantly among the groups. KDR and Flt-1 levels were high during the GA, the level being significantly higher than those during the GH and GS (P < 0.05). SDF-1 levels significantly decreased during the GH and GS compared with levels during the GA, and CXCR4 significantly increased during the GH and GS (P < 0.01). On immunostaining, ET-I -positive cells and ETAR-positive cells were found in the endothelium, vascular smooth muscle and gastric epithelium, and CXCR4-positive cells were found in the endothelium and gastric epithelium during the GH and GS. Our results suggest that VEGF receptors are mainly expressed early in ulcer development and participate in the initial stage of angiogenesis. SDF-1 receptors and ETAR are primarily expressed during the GH and GS and are involved in vascular maturation and gastric mucosal regeneration during late angiogenesis.