2-Desaza-annomontine (C81) 通过抑制 CDC2 类激酶减少血管内皮生长因子受体 2 的表达来阻碍血管生成

IF 9.2 1区 医学 Q1 PERIPHERAL VASCULAR DISEASE
T. J. Zech, A. Wolf, M. Hector, I. Bischoff-Kont, G. M. Krishnathas, S. Kuntschar, T. Schmid, F. Bracher, T. Langmann, R. Fürst
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引用次数: 0

摘要

摘要 血管生成是实体瘤、湿性老年性黄斑变性和慢性炎症等各种病症进展的关键过程。目前的抗血管生成治疗仍存在一些重大缺陷,如对依赖炎症的疾病疗效有限。因此,亟需新的抗血管生成方法,而同时抑制血管生成和炎症是可取的。在这里,我们研究发现,2-desaza-annomontine(C81)是植物生物碱annomontine的一种衍生物,以前曾被证明能抑制内皮炎症,它能通过抑制CDC2样激酶(CLKs)和WNT/β-catenin信号转导来阻碍血管生成。在激光诱导的小鼠体内模型中,C81 可减少脉络膜新生血管,抑制血管内皮生长因子 A(VEGF-A)激活的小鼠主动脉环的体内萌发,并在多种功能测试中降低内皮细胞与血管生成相关的活性。CLK抑制剂和基因敲除在很大程度上可以抑制这种作用,但C81其他已知靶点的抑制剂却不能抑制这种作用。从机理上讲,CLK 抑制剂降低了血管内皮生长因子受体 2(VEGFR2)的 mRNA 和蛋白表达以及下游信号传导。部分原因是 WNT/β-catenin 通路活性降低,因为激活该通路会诱导 VEGFR2 的表达,而敲除 β-catenin 则会阻碍 VEGFR2 的表达。令人惊讶的是,没有检测到 VEGFR2 的替代剪接。总之,C81和其他CLK抑制剂可能是治疗依赖血管生成和炎症的疾病的有前途的化合物,因为它们会损害这两个过程。 图表摘要
本文章由计算机程序翻译,如有差异,请以英文原文为准。
2-Desaza-annomontine (C81) impedes angiogenesis through reduced VEGFR2 expression derived from inhibition of CDC2-like kinases

Angiogenesis is a crucial process in the progression of various pathologies, like solid tumors, wet age-related macular degeneration, and chronic inflammation. Current anti-angiogenic treatments still have major drawbacks like limited efficacy in diseases that also rely on inflammation. Therefore, new anti-angiogenic approaches are sorely needed, and simultaneous inhibition of angiogenesis and inflammation is desirable. Here, we show that 2-desaza-annomontine (C81), a derivative of the plant alkaloid annomontine previously shown to inhibit endothelial inflammation, impedes angiogenesis by inhibiting CDC2-like kinases (CLKs) and WNT/β-catenin signaling. C81 reduced choroidal neovascularization in a laser-induced murine in vivo model, inhibited sprouting from vascular endothelial growth factor A (VEGF-A)-activated murine aortic rings ex vivo, and reduced angiogenesis-related activities of endothelial cells in multiple functional assays. This was largely phenocopied by CLK inhibitors and knockdowns, but not by inhibitors of the other known targets of C81. Mechanistically, CLK inhibition reduced VEGF receptor 2 (VEGFR2) mRNA and protein expression as well as downstream signaling. This was partly caused by a reduction of WNT/β-catenin pathway activity, as activating the pathway induced, while β-catenin knockdown impeded VEGFR2 expression. Surprisingly, alternative splicing of VEGFR2 was not detected. In summary, C81 and other CLK inhibitors could be promising compounds in the treatment of diseases that depend on angiogenesis and inflammation due to their impairment of both processes.

Graphical abstract

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来源期刊
Angiogenesis
Angiogenesis PERIPHERAL VASCULAR DISEASE-
CiteScore
21.90
自引率
8.20%
发文量
37
审稿时长
6-12 weeks
期刊介绍: Angiogenesis, a renowned international journal, seeks to publish high-quality original articles and reviews on the cellular and molecular mechanisms governing angiogenesis in both normal and pathological conditions. By serving as a primary platform for swift communication within the field of angiogenesis research, this multidisciplinary journal showcases pioneering experimental studies utilizing molecular techniques, in vitro methods, animal models, and clinical investigations into angiogenic diseases. Furthermore, Angiogenesis sheds light on cutting-edge therapeutic strategies for promoting or inhibiting angiogenesis, while also highlighting fresh markers and techniques for disease diagnosis and prognosis.
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