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2-Desaza-annomontine (C81) impedes angiogenesis through reduced VEGFR2 expression derived from inhibition of CDC2-like kinases

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Title: 2-Desaza-annomontine (C81) impedes angiogenesis through reduced VEGFR2 expression derived from inhibition of CDC2-like kinases
Authors: T. J. Zech, A. Wolf, M. Hector, I. Bischoff-Kont, G. M. Krishnathas, S. Kuntschar, T. Schmid, F. Bracher, T. Langmann, R. Fürst
Source: Angiogenesis
Publisher Information: Springer Science and Business Media LLC, 2024.
Publication Year: 2024
Subject Terms: Inflammation, Vascular Endothelial Growth Factor A, 0301 basic medicine, Original Paper, 0303 health sciences, Angiogenesis Inhibitors/pharmacology [MeSH], Endothelial Cells/metabolism [MeSH], beta Catenin/metabolism [MeSH], Kinase inhibitor, CDC-2-like-kinases, Carbolines [MeSH], Humans [MeSH], Inflammation [MeSH], Human Umbilical Vein Endothelial Cells/metabolism [MeSH], Splicing, Animals [MeSH], Angiogenesis [MeSH], Neovascularization, Pathologic/drug therapy [MeSH], WNT-signaling, Wnt Signaling Pathway [MeSH], Mice [MeSH], Vascular Endothelial Growth Factor A/metabolism [MeSH], Natural product, Pyrimidines [MeSH], Angiogenesis, Vascular Endothelial Growth Factor Receptor-2/metabolism [MeSH], Neovascularization, Pathologic, Endothelial Cells, Angiogenesis Inhibitors, Vascular Endothelial Growth Factor Receptor-2, Mice, 03 medical and health sciences, Pyrimidines, Human Umbilical Vein Endothelial Cells, Animals, Humans, Wnt Signaling Pathway, beta Catenin, Carbolines
Description: 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
Document Type: Article
Other literature type
Language: English
ISSN: 1573-7209
0969-6970
DOI: 10.1007/s10456-024-09906-y
Access URL: https://pubmed.ncbi.nlm.nih.gov/38403816
https://repository.publisso.de/resource/frl:6518611
Rights: CC BY
Accession Number: edsair.doi.dedup.....4a4830eec526302307515ff97a4ea2d3
Database: OpenAIRE
Description
Abstract: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
ISSN:15737209
09696970
DOI:10.1007/s10456-024-09906-y