Abstract
The lymphatic vascular system plays important roles in the control of tissue fluid homeostasis and immune responses. While VEGF-A-induced angiogenesis promotes hair follicle (HF) growth, the potential role of lymphatic vessels (LVs) in HF cycling has remained unknown. In this study, we found that LVs are localized in close proximity to the HF bulge area throughout the postnatal and depilation-induced hair cycle in mice and that a network of LVs directly connects the individual HFs. Increased LV density in the skin of K14-VEGF-C transgenic mice was associated with prolongation of anagen HF growth. Conversely, HF entry into the catagen phase was accelerated in K14-sVEGFR3 transgenic mice that lack cutaneous LVs. Importantly, repeated intradermal injections of VEGF-C promoted hair growth in mice. Conditioned media from lymphatic endothelial cells promoted human dermal papilla cell (DPC) growth and expression of IGF-1 and alkaline phosphatase, both activators of DPCs. Our results reveal an unexpected role of LVs in coordinating and promoting HF growth and identify potential new therapeutic strategies for hair loss-associated conditions.
Highlights
The hair follicle (HF) is a mini-organ of the skin that continuously cycles through rapid growth, apoptosis-driven regression and relative quiescence [1]
This finding was confirmed by tissue whole-mount stainings for LYVE-1 and keratin 15, followed by light-sheet microscopy, revealing precollecting vessels that extended along HFs during the anagen phase (S1 Video) but not during the telogen phase (S2 Video)
To investigate whether HF-associated lymphatic vessels (LVs) might have a functional role in HF growth and/or cycling, we studied depilation-induced hair regeneration in female keratin 14 (K14)-vascular endothelial growth factor (VEGF)-C transgenic mice that are characterized by an increased density of LVs in the skin [27] (Fig 2A)
Summary
The hair follicle (HF) is a mini-organ of the skin that continuously cycles through rapid growth (anagen phase), apoptosis-driven regression (catagen phase) and relative quiescence (telogen phase) [1]. The HF-associated blood vascular system undergoes a massive expansion during the anagen phase and a rapid involution during the catagen regression phase [2, 3]. We found that the production of vascular endothelial growth factor (VEGF)-A is upregulated during the anagen phase and that transgenic mice with increased levels of cutaneous VEGF-A have larger HFs than their wildtype littermates [4]. It has been proposed that stimulation of blood vessels by induction of VEGF-A production represents a major mechanism of action of the hair growth-promoting drug minoxidil [7].
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