title: Endothelial Cells Promote Pigmentation through Endothelin Receptor B Activation.
abstract: Findings of increased vascularization in melasma lesions and hyperpigmentation in acquired bilateral telangiectatic macules suggested a link between pigmentation and vascularization. Using high-magnification digital epiluminescence dermatoscopy, laser confocal microscopy, and histological examination, we showed that benign vascular lesions of the skin have restricted but significant hyperpigmentation compared with the surrounding skin. We then studied the role of microvascular endothelial cells in regulating skin pigmentation using an in vitro co-culture model using endothelial cells and melanocytes. These experiments showed that endothelin 1 released by microvascular endothelial cells induces increased melanogenesis signaling, characterized by microphthalmia-associated transcription factor phosphorylation, and increased tyrosinase and dopachrome tautomerase levels. Immunostaining for endothelin 1 in vascular lesions confirmed the increased expression on the basal layer of the epidermis above small vessels compared with perilesional skin. Endothelin acts through the activation of endothelin receptor B and the mitogen-activated protein kinase, extracellular signal-regulated kinase (ERK)1/2, and p38, to induce melanogenesis. Finally, culturing of reconstructed skin with microvascular endothelial cells led to increased skin pigmentation that could be prevented by inhibiting EDNRB. Taken together these results demonstrated the role of underlying microvascularization in skin pigmentation, a finding that could open new fields of research for regulating physiological pigmentation and for treating pigmentation disorders such as melasma.
authors: C3M, INSERM U1065, team 12, Nice, France.
authors: Claire
authors: C
authors: Regazzetti
authors: C3M, INSERM U1065, team 12, Nice, France.
authors: Gian Marco
authors: GM
authors: De Donatis
authors: Department of Dermatology, University Hospital Center of Nice, Nice, France.
authors: Houda Hammami
authors: HH
authors: Ghorbel
authors: Department of Pathology, University Hospital Center of Nice, Nice, France.
authors: Nathalie
authors: N
authors: Cardot-Leccia
authors: Department of Pathology, University Hospital Center of Nice, Nice, France.
authors: Damien
authors: D
authors: Ambrosetti
authors: Department of Dermatology, University Hospital Center of Nice, Nice, France; Centre de Recherche Clinique (CRC), University Hospital of Nice, Nice, France.
authors: Philippe
authors: P
authors: Bahadoran
authors: Department of Plastic Surgery, University Hospital Center of Nice, Nice, France.
authors: Bérengère
authors: B
authors: Chignon-Sicard
authors: Department of Dermatology, University Hospital Center of Nice, Nice, France.
authors: Jean-Philippe
authors: JP
authors: Lacour
authors: C3M, INSERM U1065, team 12, Nice, France.
authors: Robert
authors: R
authors: Ballotti
authors: Beiersdorf AG, Front End Innovation, Hamburg, Germany.
authors: Andre
authors: A
authors: Mahns
authors: C3M, INSERM U1065, team 12, Nice, France; Department of Dermatology, University Hospital Center of Nice, Nice, France. Electronic address: passeron@unice.fr.
authors: Thierry
authors: T
authors: Passeron
mesh_terms: D002478:Cells, Cultured; D042783:Endothelial Cells / Q000502:physiology*; D016232:Endothelins / Q000502:physiology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology; D006801:Humans; D020935:MAP Kinase Signaling System; D008543:Melanins / Q000096:biosynthesis; D008544:Melanocytes / Q000378:metabolism; D044023:Receptor, Endothelin B / Q000502:physiology*; D012880:Skin Pigmentation; D048051:p38 Mitogen-Activated Protein Kinases / Q000502:physiology
chemical_list: D016232:Endothelins; D008543:Melanins; D044023:Receptor, Endothelin B; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases