EDN1 and freckles: Melasma formation is a complex process, and the literature proposes that not only skin blood vessels and melanocytes are involved, but also senescent dermal fibroblasts, which secrete VEGF to directly stimulate neovascularization, and these newborn endothelial cells release endothelin-1, which upregulates melanogenic pathways in melanocytes (Regazzetti et al., 2015).