Section of Medical Biochemistry, Department of Biomedical and Biotechnological Sciences (Biometec), School of Medicine, University of Catania, Catania, Italy.
Institute of Biomolecular Chemistry of CNR, Catania, Italy.
J Cell Mol Med. 2019 Oct;23(10):6565-6577. doi: 10.1111/jcmm.14455. Epub 2019 Aug 1.
Angiogenesis is involved in many pathological states such as progression of tumours, retinopathy of prematurity and diabetic retinopathy. The latter is a more complex diabetic complication in which neurodegeneration plays a significant role and a leading cause of blindness. The vascular endothelial growth factor (VEGF) is a powerful pro-angiogenic factor that acts through three tyrosine kinase receptors (VEGFR-1, VEGFR-2 and VEGFR-3). In this work we studied the anti-angiogenic effect of quercetin (Q) and some of its derivates in human microvascular endothelial cells, as a blood retinal barrier model, after stimulation with VEGF-A. We found that a permethylated form of Q, namely 8MQPM, more than the simple Q, is a potent inhibitor of angiogenesis both in vitro and ex vivo. Our results showed that these compounds inhibited cell viability and migration and disrupted the formation of microvessels in rabbit aortic ring. The addition of Q and more significantly 8MQPM caused recoveries or completely re-establish the transendothelial electrical resistance (TEER) to the control values and suppressed the activation of VEGFR2 downstream signalling molecules such as AKT, extracellular signal-regulated kinase, and c-Jun N-terminal kinase. Taken together, these data suggest that 8MQPM might have an important role in the contrast of angiogenesis-related diseases.
血管生成参与许多病理状态，如肿瘤的进展、早产儿视网膜病变和糖尿病性视网膜病变。后者是一种更复杂的糖尿病并发症，其中神经退行性变起着重要作用，是失明的主要原因。血管内皮生长因子（VEGF）是一种强大的促血管生成因子，通过三个酪氨酸激酶受体（VEGFR-1、VEGFR-2 和 VEGFR-3）起作用。在这项工作中，我们研究了槲皮素（Q）及其一些衍生物在人微血管内皮细胞中的抗血管生成作用，作为血视网膜屏障模型，在 VEGF-A 刺激后。我们发现 Q 的一种全甲基化形式，即 8MQPM，比简单的 Q 更能抑制体外和体内的血管生成。我们的结果表明，这些化合物抑制细胞活力和迁移，并破坏兔主动脉环中小血管的形成。添加 Q，更显著的是 8MQPM，导致恢复或完全重建跨内皮电阻（TEER）至对照值，并抑制 VEGFR2 下游信号分子如 AKT、细胞外信号调节激酶和 c-Jun N 端激酶的激活。总之，这些数据表明 8MQPM 可能在与血管生成相关的疾病的对比中具有重要作用。
