Melanocyte-secreted fibromodulin promotes an angiogenic microenvironment
Irit Adini, … , Diane R. Bielenberg, Robert J. D’Amato
Irit Adini, … , Diane R. Bielenberg, Robert J. D’Amato
Published December 20, 2013
Citation Information: J Clin Invest. 2014;124(1):425-436. https://doi.org/10.1172/JCI69404.
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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 6

FMOD induces TGFB1 secretion by endothelial cells in vivo.

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FMOD induces TGFB1 secretion by endothelial cells in vivo. (A) HMVECs tr...
(A) HMVECs treated with neutralized anti-TGFB1 overnight and HMVEC migration were assessed in response to 3 nM recombinant FMOD or control. *P = 0.00018; **P = 0.002. (B) FMOD at designated concentrations and time courses induces TGFB1 secretion, measured in pg/ml by ELISA. P < 0.0001. Experiment repeated more than 3 times. *P = 0.003; **P = 0.0002. (C–E) HMVECs treated with 0.5 nM FMOD were assessed by Western blot using antibodies against SMAD5 (C), SMAD1 (D), and TGFRII (E). β-Actin was used as a loading control. (F) HMVECs were transfected with SMAD reporter and negative and positive control and treated with recombinant FMOD or control. Dual luciferase assay was performed and values are expressed using Renilla for internal normalization. Experiments were done in triplicate and repeated at least 3 times. ***P < 0.0001. (G) Diagram showing the role of melanocytes in angiogenesis. Lower-pigmented melanocytes express higher levels of FMOD, which stimulates angiogenesis. All experiments were repeated 3 times and included 10 eyes per group in each experiment.