Lymphangiogenesis in hypercholesterolemic skin: A comparative study of xanthomatous and non-xanthomatous lesions

While hypercholesterolemia is the primary driver of atherosclerosis, emerging evidence indicates that lymphatic vessels are critical for cholesterol transport and become impaired under hyperlipidemic conditions. Xanthelasma palpebrarum, characterized by cholesterol-laden yellowish plaques on the eyelids, is a cutaneous manifestation of dyslipidemia, yet the relationship between local cholesterol accumulation and dermal lymphatic function remains elusive. Here, we compare the lymphatic vessel morphology of xanthomatous and non-xanthomatous skin lesions in patients with various levels of serum low-density lipoprotein cholesterol. Dermal lymphatic vessel abundance was positively correlated with serum low-density lipoprotein cholesterol levels in both lesion types. Elevated low-density lipoprotein cholesterol was associated with upregulated VEGF-C expression in macrophages and increased lymphatic proliferation, indicating aberrant lymphangiogenesis in hypercholesterolemic skin. These findings reveal a previously unrecognized link between systemic cholesterol metabolism and lymphatic remodeling in human skin. The observed lymphangiogenic response may represent a compensatory mechanism for impaired cholesterol clearance or may contribute to the pathogenesis of xanthoma.