Anti-VEGF- and anti-VEGF receptor-induced vascular alteration in mouse healthy tissues

Yunlong Yang, Yin Zhang, Ziquan Cao, Hong Ji, Xiaojuan Yang, Hideki Iwamoto, Eric Wahlberg, Toste Länne, Baocun Sun, Yihai Cao

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    66 Scopus citations

    Abstract

    Systemic therapy with anti-VEGF drugs such as bevacizumab is widely used for treatment of human patients with various solid tumors. However, systemic impacts of such drugs in host healthy vasculatures remain poorly understood. Here, we show that, in mice, systemic delivery of an anti-VEGF or an anti-VEGF receptor (VEGFR)-2 neutralizing antibody caused global vascular regression. Among all examined tissues, vasculatures in endocrine glands, intestinal villi, and uterus are the most affected in response to VEGF or VEGFR-2 blockades. Thyroid vascular fenestrations were virtually completely blocked by VEGF blockade, leading to marked accumulation of intraendothelial caveolae vesicles. VEGF blockade markedly increased thyroid endothelial cell apoptosis, and withdrawal of anti-VEGF resulted in full recovery of vascular density and architecture after 14 d. Prolonged anti-VEGF treatment resulted in a significant decrease of the circulating level of the predominant thyroid hormone free thyroxine, but not the minimal isoform of triiodothyronine, suggesting that chronic anti-VEGF treatment impairs thyroid functions. Conversely, VEGFR-1-specific blockade produced virtually no obvious phenotypes. These findings provide structural and functional bases of anti-VEGF-specific drug-induced side effects in relation to vascular changes in healthy tissues. Understanding anti- VEGF drug-induced vascular alterations in healthy tissues is crucial to minimize and even to avoid adverse effects produced by currently used anti-VEGF-specific drugs.

    Original languageEnglish (US)
    Pages (from-to)12018-12023
    Number of pages6
    JournalProceedings of the National Academy of Sciences of the United States of America
    Volume110
    Issue number29
    DOIs
    StatePublished - Jul 16 2013

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    Keywords

    • Angiogenesis
    • Antiangiogenic Therapy
    • Off-Tumor Targets
    • Vascular Homeostasis
    • Vessel Regression

    ASJC Scopus subject areas

    • General

    Cite this

    Yang, Y., Zhang, Y., Cao, Z., Ji, H., Yang, X., Iwamoto, H., Wahlberg, E., Länne, T., Sun, B., & Cao, Y. (2013). Anti-VEGF- and anti-VEGF receptor-induced vascular alteration in mouse healthy tissues. Proceedings of the National Academy of Sciences of the United States of America, 110(29), 12018-12023. https://doi.org/10.1073/pnas.1301331110