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Int. J. Mol. Sci. 2018, 19(1), 53; https://doi.org/10.3390/ijms19010053

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

1
College of Pharmacy, Pusan National University, Busan 609-735, Korea
2
College of Pharmacy, Yeungnam University, Gyeongsan 712-749, Korea
3
Department of Dermatology, Seoul National University College of Medicine, Seoul National University Hospital, Seoul 110-744, Korea
4
College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 151-742, Korea
5
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)
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Abstract

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
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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).

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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.

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