Diabetes mellitus characterized by hyperglycemia favors formation of advanced glycation endproducts (AGEs) capable of triggering vascular complications by interfering with imbalanced inflammation and angiogenesis to eventually impede wound-healing. Momordica charantia (MC, bitter melon) has been shown to prevent AGE formation and to promote angiogenesis in diabetic wounds in animal models. However, the mechanism underlying its effects on angiogenesis is unclear. We investigated the effects of methanolic extracts of MC pulp (MCP), flesh (MCF) and charantin (active component of MC) using an in vitro model of angiogenesis. MC extracts or low concentrations of bovine serum albumin-derived AGEs (BSA-AGEs) stimulated proliferation, migration (using wound-healing assay) and tube formation (using Matrigel™-embedded 3D culture) of bovine aortic endothelial cells (BAEC) together with increases in the phosphorylation of extracellular signal-regulated kinase (ERK)1/2, the key angiogenic signaling cytoplasmic protein. Blocking the receptor for AGEs (RAGE) inhibited low BSA-AGE- and MC extract-induced ERK1/2 phosphorylation and tube formation, indicating the crucial role of RAGE in the pro-angiogenic effects of MC extracts. Moreover, inhibitory effects of high BSA-AGE concentration on cell proliferation and migration were reduced by the addition of MC extracts, which reversed the BSA-AGE anti-angiogenic effect on tube formation. Thus, MC extracts exert direct pro-angiogenic signaling mediated via RAGE to overcome the anti-angiogenic effects of high BSA-AGEs, highlighting the biphasic RAGE-dependent mechanisms involved. This study enhances our understanding of the mechanisms underlying the pro-angiogenic effects of MC extracts in improvement of diabetes-impaired wound-healing.

中文翻译：

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苦瓜提取物可防止高级糖基化终产物在体外抑制内皮血管生成

以高血糖为特征的糖尿病有利于晚期糖基化终产物（AGEs）的形成，这些终产物能够通过干扰不平衡的炎症和血管生成而最终触发伤口愈合，从而引发血管并发症。在动物模型中，苦瓜（MC，苦瓜）已被证明可以预防AGE的形成并促进糖尿病伤口的血管生成。然而，尚不清楚其对血管生成的作用的机制。我们使用体外方法研究了MC纸浆（MCP），果肉（MCF）和charantin（MC的活性成分）的甲醇提取物的作用血管生成模型。MC提取物或低浓度的牛血清白蛋白衍生的AGEs（BSA-AGEs）刺激了牛主动脉内皮细胞（BAEC）的增殖，迁移（使用伤口愈合试验）和管形成（使用Matrigel™嵌入式3D培养）以及增加细胞外信号调节激酶（ERK）1/2，关键的血管生成信号胞质蛋白的磷酸化。阻断AGEs受体（RAGE）抑制了低BSA-AGE和MC提取物诱导的ERK1 / 2磷酸化和管形成，表明RAGE在MC提取物的促血管生成作用中具有关键作用。此外，MC提取物的加入降低了高BSA-AGE浓度对细胞增殖和迁移的抑制作用，从而逆转了BSA-AGE对管形成的抗血管生成作用。因此，通过RAGE克服高BSA-AGEs的抗血管生成作用，强调了涉及RAGE的双相依赖机制。这项研究增强了我们对MC提取物在改善糖尿病受损的伤口愈合中促血管生成作用的潜在机制的理解。