Highly pigmented melanocytes have greater expression and activity of the enzyme tyrosinase, which regulates multiple steps in melanogenesis. The melanogenesis intermediate DHI inhibits FMOD expression through as-yet-unknown mechanisms, and the increased tyrosinase activity in heavily pigmented cells corresponds with reduced expression of FMOD mRNA and protein, although melanin does not directly regulate FMOD expression. In lightly pigmented cells, the lack of tyrosinase activity enhances the production and secretion of FMOD from melanocytes, which promotes angiogenic cellular responses of nearby endothelial cells. At the level of the endothelial cell (inset), FMOD promotes activation of TGF-β receptor signaling (through SMAD phosphorylation) and upregulation of angiogenic growth factors, including VEGF and ANG2, while repressing the vascular stabilizing factor ANG1 (not shown) through unknown mechanisms. VEGF and ANG2 activate their cognate endothelial receptor tyrosine kinases, VEGFR-2 and TIE2, to induce angiogenic cellular responses.