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 3

FMOD-induced migration, proliferation and sprouting of HMVECs.

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FMOD-induced migration, proliferation and sprouting of HMVECs. (A) HMVEC...
(A) HMVEC migration in response to FMOD-neutralized CM from nonpigmented melanocytes, IgG was used as a control. (B) siRNA-mediated knockdown of FMOD was confirmed by Western blot. β-Actin was used as a loading control. (C) HMVEC migration in response to CM from nonpigmented melanocytes transfected with FMOD-specific siRNA. (D) HMVEC migration was assessed in CM from pigmented melanocytes containing 2 μM recombinant FMOD or GST. (E) HMVEC migration with recombinant FMOD or control-GST. (F) Proliferation of HMVECs with designated concentrations of FMOD was assessed by cell counting. (G) HMVECs are coated onto beads and embedded into a fibrin gel in the presence of medium alone, medium plus 1.5 nM FMOD, or medium plus VEGF-A/FGF2 (1.5 nM each). Arrows show sprouts. Scale bar: 100 μm. (H) Average number of sprouts per bead was not significantly different between 1.5 nM FMOD and positive VEGF-A/FGF2 control. Significant differences were observed between recombinant FMOD and control. (I) Percentage of sprouts with a length less than 150 μm in the presence of 1.5 nM FMOD and 1.5 nM VEGF-A+FGF2 versus those with length greater than 150 μm in the presence of FMOD or 1.5 nM VEGF-A/FGF2. 1.5 nM FMOD increased cell migration over VEGF-A/FGF2. **P < 0.001; ***P < 0.0001.