title: Melanocyte pigmentation inversely correlates with MCP-1 production and angiogenesis-inducing potential.
abstract: The incidence of certain angiogenesis-dependent diseases is higher in Caucasians than in African Americans. Angiogenesis is amplified in wound healing and cornea models in albino C57 mice compared with black C57 mice. Moreover, mouse and human melanocytes with low pigmentation stimulate endothelial cell (EC) proliferation and migration in vitro more than melanocytes with high pigmentation. This effect is due, in part, to the secretion of an angiogenic protein called fibromodulin (FMOD) from lowly pigmented melanocytes. Herein, we expand upon the mechanism contributing to increased angiogenesis in lighter skin and report that monocyte chemotactic protein-1 (MCP-1) is secreted by nonpigmented mouse melanocytes by 5- to 10-fold more than pigmented melanocytes. MCP-1 protein stimulates EC proliferation and migration in vitro and angiogenesis in vivo. Mechanistic studies determine that FMOD is upstream of MCP-1 and promotes its secretion from both melanocytes and activated ECs via stimulation of NF-κB activity. Mice injected with FMOD-neutralizing antibodies show 2.3-fold decreased levels of circulating MCP-1. Human studies confirmed that, on average, Caucasians have 2-fold higher serum levels of MCP-1 than African Americans. Taken together, this study implicates the FMOD/MCP-1 pathway in the regulation of angiogenesis by local melanocytes and suggests that melanogenic activity may protect against aberrant angiogenic diseases.
authors.affiliation: Vascular Biology Program, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Irit
authors.initials: I
authors.lastname: Adini
authors.affiliation: Vascular Biology Program, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA irit.adini@gmail.com.
authors.forename: Avner
authors.initials: A
authors.lastname: Adini
authors.affiliation: Vascular Biology Program, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Lauren
authors.initials: L
authors.lastname: Bazinet
authors.affiliation: Vascular Biology Program, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Randolph S
authors.initials: RS
authors.lastname: Watnick
authors.affiliation: Vascular Biology Program, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Diane R
authors.initials: DR
authors.lastname: Bielenberg
authors.affiliation: Vascular Biology Program, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: D'Amato
mesh_terms: D001741:Black or African American; D043925:Angiogenesis Inducing Agents / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000378:metabolism*; D042783:Endothelial Cells / Q000166:cytology; D004797:Enzyme-Linked Immunosorbent Assay; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D000071235:Fibromodulin; D006801:Humans; D008544:Melanocytes / Q000166:cytology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008833:Microcirculation; D016328:NF-kappa B / Q000378:metabolism; D009389:Neovascularization, Pathologic; D010858:Pigmentation; D011509:Proteoglycans / Q000378:metabolism; D012880:Skin Pigmentation
chemical_list: D043925:Angiogenesis Inducing Agents; C111835:CCL2 protein, human; D018932:Chemokine CCL2; D016326:Extracellular Matrix Proteins; C000604330:FMOD protein, human; C000604332:Fmod protein, mouse; D016328:NF-kappa B; D011509:Proteoglycans; D000071235:Fibromodulin
keywords: FMOD; NF-κB; endothelial cells; vascular biology