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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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 1

Effect of pigmented and nonpigmented melanocytes on angiogenesis.

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Effect of pigmented and nonpigmented melanocytes on angiogenesis. (A) Co...
(A) Corneal neovascular response in different inbred mouse strains induced by corneal implantation of FGF2 pellets (P) in C57-albino mice (left) with hyphema formation (H) and C57BL mice (right). The experiment included 10 eyes per group. (B) Iris neovascularization visualized with FITC–BS-1 lectin. Scale bars: 500 μm. The experiment included 10 eyes per group. (C) Quantification of iris vessel density of C57-albino versus C57BL. Experiment included 10 eyes per group. (D) Normal skin vessel density in C57-albino and C57BL mice labeled with CD31 antibody. Scale bar: 20 μm. (E) Angiogenesis during wound healing in ear skin. Blood vessels were perfused with FITC-conjugated BS-1 lectin (green) and photographed. Scale bars: 10 μm. The experiment included 5 wounds per group. (F) Analysis of microvessel density in albino ear skin. (G) Migration of HMVECs to CM from albino (CM-NP) and pigmented (CM-P) melanocytes. (H) Migration of HMVECs to CM from pigmented melanocytes grown in the presence and absence of tyrosine. (I) Migration of HMVECs to CM from human melanocytes (mixed European descent and African-American) through Transwells. (J) HMVEC proliferation in response to CM from nonpigmented or pigmented melanocytes for 24 hours; analysis by WST-1 at 450 O.D. (K) HMVECs incubated with CM from human melanocytes (mixed European descent and African-American) for 24 hours, followed by proliferation analysis with WST-1 at 450 O.D. All experiments were repeated at least 3 times. *P < 0.01; **P < 0.001; ***P < 0.0001.