Next Article in Journal
Development of Antibody Therapeutics against Flaviviruses
Previous Article in Journal
Oncomirs Expression Profiling in Uterine Leiomyosarcoma Cells
Article Menu
Issue 1 (January) cover image

Export Article

Open AccessArticle
Int. J. Mol. Sci. 2018, 19(1), 53;

Minoxidil Induction of VEGF Is Mediated by Inhibition of HIF-Prolyl Hydroxylase

College of Pharmacy, Pusan National University, Busan 609-735, Korea
College of Pharmacy, Yeungnam University, Gyeongsan 712-749, Korea
Department of Dermatology, Seoul National University College of Medicine, Seoul National University Hospital, Seoul 110-744, Korea
College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 151-742, Korea
Department of Molecular Biology, College of Natural Science, Pusan National University, Busan 609-735, Korea
These authors contributed equally to this work.
Author to whom correspondence should be addressed.
Received: 22 November 2017 / Revised: 16 December 2017 / Accepted: 20 December 2017 / Published: 25 December 2017
(This article belongs to the Section Biochemistry)
Full-Text   |   PDF [2790 KB, uploaded 25 December 2017]   |  


The topical application of minoxidil may achieve millimolar concentrations in the skin. We investigated whether millimolar minoxidil could induce vascular endothelial growth factor (VEGF), a possible effector for minoxidil-mediated hair growth, and how it occurred at the molecular level. Cell-based experiments were performed to investigate a molecular mechanism underlying the millimolar minoxidil induction of VEGF. The inhibitory effect of minoxidil on hypoxia-inducible factor (HIF) prolyl hydroxylase-2 (PHD-2) was tested by an in vitro von Hippel–Lindau protein (VHL) binding assay. To examine the angiogenic potential of millimolar minoxidil, a chorioallantoic membrane (CAM) assay was used. In human keratinocytes and dermal papilla cells, millimolar minoxidil increased the secretion of VEGF, which was not attenuated by a specific adenosine receptor antagonist that inhibits the micromolar minoxidil induction of VEGF. Millimolar minoxidil induced hypoxia-inducible factor-1α (HIF-1α), and the induction of VEGF was dependent on HIF-1. Moreover, minoxidil applied to the dorsal area of mice increased HIF-1α and VEGF in the skin. In an in vitro VHL binding assay, minoxidil directly inhibited PHD-2, thus preventing the hydroxylation of cellular HIF-1α and VHL-dependent proteasome degradation and resulting in the stabilization of HIF-1α protein. Minoxidil inhibition of PHD-2 was reversed by ascorbate, a cofactor of PHD-2, and the minoxidil induction of cellular HIF-1α was abrogated by the cofactor. Millimolar minoxidil promoted angiogenesis in the CAM assay, an in vivo angiogenic test, and this was nullified by the specific inhibition of VEGF. Our data demonstrate that PHD may be the molecular target for millimolar minoxidil-mediated VEGF induction via HIF-1. View Full-Text
Keywords: hypoxia inducible factor; minoxidil; vascular endothelial growth factor; angiogenesis; von Hippel–Lindau protein hypoxia inducible factor; minoxidil; vascular endothelial growth factor; angiogenesis; von Hippel–Lindau protein

Graphical abstract

This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).

Supplementary material


Share & Cite This Article

MDPI and ACS Style

Yum, S.; Jeong, S.; Kim, D.; Lee, S.; Kim, W.; Yoo, J.-W.; Kim, J.-A.; Kwon, O.S.; Kim, D.-D.; Min, D.S.; Jung, Y. Minoxidil Induction of VEGF Is Mediated by Inhibition of HIF-Prolyl Hydroxylase. Int. J. Mol. Sci. 2018, 19, 53.

Show more citation formats Show less citations formats

Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.

Related Articles

Article Metrics

Article Access Statistics



[Return to top]
Int. J. Mol. Sci. EISSN 1422-0067 Published by MDPI AG, Basel, Switzerland RSS E-Mail Table of Contents Alert
Back to Top