Minoxidil Induction Of Vegf Is Mediated By Inhibition Of Hif-prolyl Hydroxylase

[InBeforeTheCure]

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

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.

 

[thisis]

Interesting, thank you for the post.

Would you say this is a significant reason for minoxidil working?
I've seen some other articles on what minoxidil does, so I'm wondering whether it might be downstream of inhibiting PHD-2
Can we find other PHD-2 inhibitors maybe without the side effects of minoxidil?

Not to derail, but I've seen you've posted on genetic expression in Androgenetic Alopecia.
ARNTL2 is 12x downregulated compared to non-balding. One of the most Downregulated in a particular study.
HIF-1alpha dimerizes with ARNTL(NOT arntl2, but they are parralelogs according to wiki) to induce VEGF expression

https://aopwiki.org/aops/150
According to this, suggested, aryl hydrocarbon receptor AhR overactivity robs HIF-1alpha from its partner ARNT.
Is it possible there is some AhR overactivity and the body is downregulating ARNT2 to limit it, I'm interested in your take of what other genes AhR might be related to in terms of balding.

 

[InBeforeTheCure]

Interesting, thank you for the post.

Would you say this is a significant reason for minoxidil working?
I've seen some other articles on what minoxidil does, so I'm wondering whether it might be downstream of inhibiting PHD-2
Can we find other PHD-2 inhibitors maybe without the side effects of minoxidil?

Re: Would you say this is a significant reason for minoxidil working?

Probably not, actually.

From the paper:

We next examined the molecular mechanism underlying millimolar minoxidil-mediated HIF-1 activation. To exclude any involvement of potassium channels in the minoxidil induction of HIF-1α, DPCs and HaCaT cells were treated with diazoxide, another potassium channel activator. As shown in Figure 3A, diazoxide did not induce HIF-1α protein.

Although potassium channel opening is a major pharmacologic effect of minoxidil, diazoxide, another potassium channel opener, did not induce HIF-1α, ruling out the involvement of the channel in HIF-1α induction. In parallel with this result, minoxidil sulfate (100 and 200 μM), the active metabolite of minoxidil that acts on the potassium channel [5,39], did not inhibit PHD or induce HIF-1α in the skin cells. This molecular effect may place minoxidil in a unique position among potassium channel openers that stimulate hair growth, including diazoxide, pinacidil, and minoxidil [5]

Given that oral minoxidil, which cannot achieve a millimolar level of minoxidil in the scalp skin, and topical diazoxide (3%) are able to promote hair growth [5,42], it is not clear, for now, how much the cellular effects by millimolar minoxidil contribute to topical minoxidil-mediated hair growth. Further investigation is needed to clarify the pharmacological role of the cellular effects in hair growth.

Since minoxidil sulfate (which opens potassium channels) is the metabolite responsible for hair growth, and other potassium channel openers like diazoxide also stimulate hair growth, this mechanism probably doesn't contribute much.

Not to derail, but I've seen you've posted on genetic expression in Androgenetic Alopecia.
ARNTL2 is 12x downregulated compared to non-balding. One of the most Downregulated in a particular study.
HIF-1alpha dimerizes with ARNTL(NOT arntl2, but they are parralelogs according to wiki) to induce VEGF expression

https://aopwiki.org/aops/150
According to this, suggested, aryl hydrocarbon receptor AhR overactivity robs HIF-1alpha from its partner ARNT.
Is it possible there is some AhR overactivity and the body is downregulating ARNT2 to limit it, I'm interested in your take of what other genes AhR might be related to in terms of balding.

There's a contradictory result (there often are) from another microarray dataset where median expression of ARNTL2 is higher in bald scalp, but with wildly varying values for each person. ARNTL2 is one of the circadian clock genes, also involved in hair cycling (here is a study if you're interested). Maybe there's some crosstalk between the clock genes and HIF-1 in the hair cycle as well?