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 AfricanAmericans. 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. Relative to what is found in light-skinned individuals of mixed European descent, exudative AMD is 55% less frequent in African-Americans and 46% less frequent in Asian-Americans. These findings support the hypothesis that lower pigmentation is a risk factor for neovascular AMD (1-3). Studies examining the correlation between race, ethnicity, and incidence of uveal melanoma indicate an influence of iris color on the disease. The frequency of uveal melanoma is highest in light-skinned individuals of mixed European descent, followed by Hispanics, Asians, and African-Americans, with an 18:1 ratio of incidence between light-skinned individuals of mixed European descent and African-Americans (4-6). Similar to the trend of occurrence seen with wet AMD, cutaneous melanoma and infantile hemangioma are much more prevalent in light-skinned individuals of mixed European descent than AfricanAmericans. These facts suggest that low levels of melanin correlate with the development of angiogenic ocular and skin diseases. Since intracellular pigment levels of retinal pigment epithelium (RPE) cells do not differ greatly among races, our studies focused on melanocytes, the main source of ocular pigment.

Expression of fibromodulin in carotid atherosclerotic plaques is associated with diabetes and cerebrovascular events

“…Angiogenesis in vitro as well as in vivo is promoted by fibromodulin, whereas an inhibitory effect has been reported for lumican. [32][33][34][35][36] The connection between diabetes and CV disease is well-documented. [37][38][39] Metabolic abnormalities such as chronic hyperglycemia, dyslipidemia and insulin resistance render arteries more susceptible to atherosclerosis.…”

More than skin deep: connecting melanocyte pigmentation and angiogenic diseases

“…VEGF and ANG2 activate their cognate endothelial receptor tyrosine kinases, VEGFR-2 and TIE2, to induce angiogenic cellular responses. ment with an inhibitory TGF-β antibody (5). Exogenous FMOD induced expression of TGF-βRII, SMAD1, and SMAD5 in ECs, implying an autocrine loop in which FMOD upregulates TGF-β and its receptor, leading to activation of TGF-β signaling and vascular growth (Figure 1).…”

“…In order to identify the specific factor or factors responsible for the observed effects, the authors performed a targeted microarray that compared expression of genes predicted to encode secreted proteins in pigmented and nonpigmented melanocytes (5). Fibromodulin (FMOD), an ECM protein of the small leucine-rich proteoglycan (SLRP) family, was expressed to a much greater degree in nonpigmented melanocytes both in vitro and in vivo.…”

“…In this regard, the results of Adini et al (5) suggest that FMOD expression is an important biomarker of angiogenic disease susceptibility in the eyes, skin, and possibly other organs. For example, differential gene expression analysis revealed that FMOD is upregulated in glioblastoma, a highly malignant and angiogenic brain tumor, compared with the relatively benign pilocytic astrocytoma (16).…”

Paracrine crosstalk between endothelial cells and melanocytes through clusterin to inhibit pigmentation

“…Very recently, it was suggested that cutaneous vasculature plays a role in regulating skin pigmentation and perhaps its dysfunction in pigmentary diseases [4,5]. Conversely, a regulatory function of melanocytes on vascularization was also discovered, suggesting paracrine crosstalk between endothelial cells and melanocytes [6]. Endothelial cells produce prostaglandins, nitric oxide or endothelin-1 for pigmentation regulation [7].…”