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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 Article has an altmetric score of 23

Melanocyte-secreted fibromodulin promotes an angiogenic microenvironment

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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 4

FMOD induces endothelial cell migration in vivo.

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FMOD induces endothelial cell migration in vivo.
(A) HVMECs combined wit...
(A) HVMECs combined with BM-MSC (10:1) with or without recombinant h-FMOD were mixed with Matrigel. Perfused vessels were labeled with human-specific rhodamine-labeled lectin and visualized with confocal microscopy; n = 6 plugs per group; experiment repeated 3 times. Original magnification, ×5. (B and C) Migration of host endothelial cells into Matrigel plugs containing nonpigmented melanocytes neutralized by anti FMOD or IgG as a control. Cells were stained for CD31 and CD45 and analyzed by FACS; n = 10 per group (C). (D) The corneal micropocket assay was performed with pellets containing 1.69 μM of FMOD, 1.69 μM GST, or 5.2 μM VEGF-A. FMOD versus control was significantly different. No significant difference in VA was found between FMOD and VEGF-A. The experiment was repeated 3 times and included 10 eyes per group in each experiment. (E) FMOD stimulated longer vessels than VEGF-A. (F) FMOD (2 μM) promotes angiogenesis in wound healing in ear skin of C57BL/6J mice; blood vessels visualized by FITC-conjugated dextran (green). Scale bar: 500 μm. (G) Quantification of blood vessel density; n = 5 mice per group; 2 punches per mouse. (H) Recombinant FMOD (1.19 μM) or control-GST injected into the vitreous of 4-day-old pups; n = 5 mice per group. On day 7, retinas were dissected and labeled (Alexa Fluor 594–conjugated isolectin). Scale bar: 1 nm. Original magnification, ×5. (I) Neovascular density was assessed by quantifying the capillary junctions within 4 equal areas (ImageJ). (J) Avascular retina was calculated as percentage of total retinal area quantified (ImageJ); n = 9 in each group, experiment was repeated twice. **P < 0.001; ***P < 0.0001.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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