Melanocyte-secreted fibromodulin promotes an angiogenic microenvironment
Irit Adini, Kaustabh Ghosh, Avner Adini, Zai-Long Chi, Takeru Yoshimura, Ofra Benny, Kip M. Connor, Michael S. Rogers, Lauren Bazinet, Amy E. Birsner, Diane R. Bielenberg, Robert J. D’Amato
Irit Adini, Kaustabh Ghosh, Avner Adini, Zai-Long Chi, Takeru Yoshimura, Ofra Benny, Kip M. Connor, Michael S. Rogers, Lauren Bazinet, Amy E. Birsner, Diane R. Bielenberg, Robert J. D’Amato
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Research Article

Melanocyte-secreted fibromodulin promotes an angiogenic microenvironment

Abstract

Studies have established that pigmentation can provide strong, protective effects against certain human diseases. For example, angiogenesis-dependent diseases such as wet age-related macular degeneration and infantile hemangioma are more common in light-skinned individuals of mixed European descent than in African-Americans. Here we found that melanocytes from light-skinned humans and albino mice secrete high levels of fibromodulin (FMOD), which we determined to be a potent angiogenic factor. FMOD treatment stimulated angiogenesis in numerous in vivo systems, including laser-induced choroidal neovascularization, growth factor–induced corneal neovascularization, wound healing, and Matrigel plug assays. Additionally, FMOD enhanced vascular sprouting during normal retinal development. Deletion of Fmod in albino mice resulted in a marked reduction in the amount of neovascularization induced by retinal vein occlusion, corneal growth factor pellets, and Matrigel plugs. Our data implicate the melanocyte-secreted factor FMOD as a key regulator of angiogenesis and suggest an underlying mechanism for epidemiological differences between light-skinned individuals of mixed European descent and African-Americans. Furthermore, inhibition of FMOD in humans has potential as a therapeutic strategy for treating angiogenesis-dependent diseases.

Authors

Irit Adini, Kaustabh Ghosh, Avner Adini, Zai-Long Chi, Takeru Yoshimura, Ofra Benny, Kip M. Connor, Michael S. Rogers, Lauren Bazinet, Amy E. Birsner, Diane R. Bielenberg, Robert J. D’Amato

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Figure 5

FMOD enhances CNV formation and induces endothelial cell migration in vivo.

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FMOD enhances CNV formation and induces endothelial cell migration in vi...
(A) CNV lesions were induced by subretinal laser burns around the optic disc. After laser treatment, intravitreal injection of 35 ng/0.5 μl/eye rh-FMOD or control-GST was performed. Representative images of CNV lesions stained with lectin-FITC are shown. Original magnification, ×10. (B) Data are presented as mean pixel number ± SEM. t test. n = 30–40. (C) To quantify the effect of Fmod-KO (Fmod–/– in C57-albino compared with Fmod+/+ C57-albino) on migration of host endothelial cells into Matrigel plugs containing 500 ng/ml FGF-2, cells were stained for CD31 and CD45 and analyzed by FACS. n = 10. Each experiment was repeated 3 times. (D) Iris neovascularization after FGF2 corneal pellet implantation was visualized with FITC–BS-1 lectin. Scale bar: 500 μm. (E) Quantification of iris VA of C57-albino versus Fmod–/– albino. (F) Quantification of total iris vessel length of C57-albino versus Fmod–/– albino. (G) Quantification of iris branching index of C57-albino versus Fmod–/– albino. (H) RVO lesions were induced by laser burns around the optic nerve. After laser treatment, images of iris neovascularization stained with lectin-GSII were analyzed. (I) Quantification of iris VA of C57-albino versus Fmod–/– albino. (J) Quantification of total iris vessel length of C57-albino versus Fmod–/– albino. **P < 0.001; ***P < 0.0001.