Androgen Receptor-Mediated Paracrine Signaling Induces Regression of Blood Vessels in the Dermal Papilla in Androgenetic Alopecia

J Invest Dermatol. 2022 Aug;142(:2088-2099.e9. doi: 10.1016/j.jid.2022.01.003. Epub 2022 Jan 14.
Androgen Receptor-Mediated Paracrine Signaling Induces Regression of Blood Vessels in the Dermal Papilla in Androgenetic Alopecia
Zhili Deng 1, Mengting Chen 1, Fangfen Liu 1, Yunying Wang 2, San Xu 1, Ke Sha 1, Qinqin Peng 1, Zheng Wu 1, Wenqin Xiao 1, Tangxiele Liu 1, Hongfu Xie 1, Ji Li 3

Androgenetic alopecia (AGA), also known as male pattern baldness, is associated with androgen and androgen receptor (AR) signaling; however, the pathogenesis of AGA remains largely unknown. In this study, we show that nuclear localization of AR is elevated in the dermal papilla (DP) of balding scalp in patients with AGA. Transcriptome analysis identifies microvascular abnormalities in the DP of balding scalp compared with nonbalding scalp of patients with AGA. We provide further evidence that blood vessels regress in the DP of balding scalp at the early stage of hair follicle miniaturization in AGA development. Consistently, we find that microvascular vessels accumulate around the DP on anagen initiation, and angiogenesis is required for hair regeneration in mice. Mechanistically, we show that AR-mediated paracrine signaling, mainly TGFβ signaling, from DP cells induces apoptosis of microvascular endothelial cells in the DP of balding scalp of AGA. These findings define a role of AR-mediated regression of blood vessels in DP in AGA and support the notion that early anti-AR treatment is better than late treatment.

"Blood vessels regress in DP of balding scalp at the early stage of HF miniaturization in AGA

To examine what happens to blood vessels in balding DPs, we observed DPs with stereoscope after isolation. Unexpectedly, although blood vessels were normal in nonbalding DPs, they vanished in most DPs of balding scalps in AGA (Figure 3a and b). To further confirm these findings, we performed CD31 immunostaining to label endothelial cells of blood vessels. Consistent with the observations with stereoscope, we showed that DPs containing CD31+ vessels were significantly decreased in balding scalps compared with nonbalding scalps of patients with AGA and normal frontal scalps of healthy individuals (Figure 3c and d and Supplementary Figure S3a). Because the blood vessels regressed in balding DPs, we wondered whether the blood vessels surrounding HFs were affected in balding scalps in AGA. Our results showed that there was no obvious change in blood vessels between balding and nonbalding scalps in AGA (Supplementary Figure S3b). Next, we attempted to determine the stage of AGA development at which the regression of blood vessels occurred. By comparing the diameter of HFs with or without CD31+ vessel–DP from both balding and nonbalding scalps, we found that the size of HFs with CD31+ DP in balding scalps had no significant difference when compared with that of DPs in nonbalding scalps. However, the size of HFs without CD31+ DP in balding scalps was remarkably declined compared with that in the other three groups (Figure 3e and f), implying that the regression of blood vessels occurred at the early stage of HF miniaturization (i.e., the stage at which HF miniaturization begins) in the development of AGA. To further verify the hypothesis that the size of HFs is associated with the existence of blood vessels in DP, we detected the blood vessels in DPs of nasal side skin, which contains both big size vibrissae and small size HFs in mice. Our results showed that there existed obvious CD31+ vessels in the DPs of vibrissae but not in the DPs of the small HFs (Supplementary Figure S3c). Collectively, these results suggest that blood vessels vanish in DP of balding scalp at the early stage of HF miniaturization in AGA development."

Long form: https://www.jidonline.org/article/S0022-202X(22)00009-4/fulltext

niacine and restoring healthy NO production, meanwhile focusing on endothelium with arginine would tackle this?

Zaphod wrote:niacine and restoring healthy NO production, meanwhile focusing on endothelium with arginine would tackle this?

Yes, probably so.

Niacin (Vitamin B3) is known to boost NO production, which helps relax blood vessels and improve blood flow. This could potentially counteract the microvascular abnormalities observed in AGA by enhancing blood supply to the hair follicles.

L-arginine, an amino acid, is a precursor for NO synthesis in endothelial cells. It plays a crucial role in maintaining vascular tone and overall cardiovascular health Supplementing with L-arginine could support endothelial function and improve blood flow to the scalp, potentially mitigating the effects of AR-mediated signaling in AGA.

That said, through time some of these do not work as well, such as "plain L-Arginine" or with the co-factors.

I will be experimenting with Agmatine sulfate and directly compare it with "standard" L-arginine along with "activators" or "enhancers" to keep the nitric oxide working longer.

L-arginine is a direct precursor to nitric oxide. It is converted into NO by nitric oxide synthase (NOS) enzymes, which helps to dilate blood vessels and improve blood flow.

Whereas Agmatine sulfate is a metabolite of L-arginine and has been shown to activate endothelial nitric oxide synthase (eNOS), which also leads to increased NO production.

My guess is, Agmatine sulfate might offer additional benefits beyond just NO production. It's a type of decarboxylated arginine.

If anyone has some ideas in this area, please post.

Caustic, LLLT from the energetical standpoint, and antioxidant load after high UV exposure, which is extremely beneficial for NO, might be ideas worth considering.

Besides this, I believe L-arginine when taken, would be best taken with a proper ratio with citrulline. I believe we have a relationship where more is not always merrier. It is trial and error.

I am increasingly a fan of research that deals with cross cell wall bioelectricity, and electrical cell-to-cell communication. The gradients are mediated with voltage gated channels, but the junctions between the cell exist enabling a lot of regenerative potential.

Will maybe create a larger-scale post on the topic. It is possibly why PEMF works on many many inflammatory conditions. I am having a PEMF device in redesign at my firm, which is extremely powerful. So powerful that it should be illegal for good reason. What i notice while using, is boost of blood flow. Even to the point that no stimulus is required for a strong erection. I do not recall such things since my teens.

https://n1o1.com/?sld=reverse

this is using sodium nitrite

I had recommended someone use PEMF over a decade ago. I might get the chance to use one soon.

Some months ago, I tried out various dosages of potassium nitrate (not sodium), however it wasn't too apparent on the effect.

I did trial some Agmatine Suflate, and quite happy with the results versus various types of L-Citrulline and L-Arginine related products.

At the moment I am experimenting with the peptide Vesugen:

https://www.youtube.com/watch?v=fi1xKOb-nwo

I combine it with Pinealon and Thymolin.

Atlas wrote:At the moment I am experimenting with the peptide Vesugen:

https://www.youtube.com/watch?v=fi1xKOb-nwo

I combine it with Pinealon and Thymolin.

Great info!

I'll be looking into this.

The effects on my mental clarity are extrem although I was pretty „sharp“ before I started to take peptides. Epitalon is also interesting, I use subc. or i.m. injections. Typically I buy the peptides directly from biotech companies (much much cheaper).