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Bp5250 inhibits vascular endothelial growth factor-induced angiogenesis and HIF-1α expression on endothelial cells

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Abstract

Angiogenesis plays a critical role in many physiological and pathological phenomena. A number of anti-angiogenesis drugs have been used in the clinical treatment of diseases such as malignant tumors and macular degeneration. Vascular endothelial growth factor (VEGF), the major pro-angiogenesis factor, is known to stimulate various steps of endothelial angiogenic activity, such as proliferation, migration, and differentiation into vessel-like tubes. In this study, we tested the effects of bp5250 on the angiogenesis of human umbilical endothelial cells (HUVECs). Bp5250 suppressed VEGF-induced endothelial cell proliferation by triggering apoptosis, and reduced endothelial cell migration toward VEGF. Bp5250 also decreased VEGF-stimulated tube formation and rat aortic ring sprouting on Matrigel in a concentration-dependent manner. In the VEGF-activated signaling pathways, bp5250 decreased the phosphorylation of ERK, p38, PI3K-AKT, Src, and FAK and also reduced the activation of the cytoskeleton-associated Rho family, all in a concentration-dependent manner. Bp5250 also attenuated the hypoxia-inducible factor-1α (HIF-1α) and VEGF-stimulated mRNA expression of HUVECs under the hypoxic condition. In vivo, angiogenesis was restrained by a daily intraperitoneal administration of bp5250 in a dose-dependent manner (1–3 mg/kg/d) in the Matrigel plug implantation assay. These results indicate that bp5250 is a potential candidate for developing anti-angiogenic agents.

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Acknowledgments

This work was supported by grants from the National Science Council (NSC97-2323-B-002-008, NSC98-2323-B-002-009, NSC99-2323-B-002-004 and NSC99-2320-B-039-010-MY3) of Taiwan.

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The authors state that there is no conflict of interest.

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Authors and Affiliations

  1. Graduate Institute of Pharmacology, College of Medicine, National Taiwan University, No.1, Sec. 1, Jen-Ai Road, Taipei, Taiwan

    Kuan-Ting Lin & Tur-Fu Huang

  2. Graduate Institute of Pharmaceutical Chemistry, China Medical University, No.91, Hsueh-Shih Road, Taichung, Taiwan

    Jin-Cherng Lien & Sheng-Chu Kuo

  3. Institute of Pharmacology and Toxicology, Tzu Chi University, No.701, Sec. 3, Zhong-Yang Road, Hualien, Taiwan

    Ching-Hu Chung

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  1. Kuan-Ting Lin
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Correspondence to Jin-Cherng Lien or Tur-Fu Huang.

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Lin, KT., Lien, JC., Chung, CH. et al. Bp5250 inhibits vascular endothelial growth factor-induced angiogenesis and HIF-1α expression on endothelial cells. Naunyn-Schmiedeberg's Arch Pharmacol 385, 39–49 (2012). https://doi.org/10.1007/s00210-011-0690-2

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