Enhanced Lymph Vessel Density, Remodeling, and Inflammation Are Reflected by Gene Expression Signatures in Dermal Lymphatic Endothelial Cells in Type 2 Diabetes

Abstract

Type 2 diabetes is associated with microvascular damage that causes frequent infections in the skin and chronic ulcers as a result of impaired wound healing. To trace the pathological changes, we performed a comprehensive analysis of lymphatic vessels in the skin of type 2 diabetic versus nondiabetic patients. The dermis revealed enhanced lymphatic vessel density, and transcriptional profiling of ex vivo isolated lymphatic endothelial cells (LECs) identified 160 genes differentially expressed between type 2 diabetic and nondiabetic LECs. Bioinformatic analysis of deregulated genes uncovered sets functionally related to inflammation, lymphatic vessel remodeling, lymphangiogenesis, and lipid and small molecule transport. Furthermore, we traced CD68+ macrophage accumulation and concomitant upregulation of tumor necrosis factor-α (TNF-α) levels in type 2 diabetic skin. TNF-α treatment of LECs and its specific blockade in vitro reproduced differential regulation of a gene set that led to enhanced LEC mobility and macrophage attachment, which was mediated by the LEC-derived chemokine CXCL10. This study identifies lymph vessel gene signatures directly correlated with type 2 diabetes skin manifestations. In addition, we provide evidence for paracrine cross-talk fostering macrophage recruitment to LECs as one pathophysiological process that might contribute to aberrant lymphangiogenesis and persistent inflammation in the skin.

Inflammation-associated lymphangiogenesis: a double-edged sword?

“…This resulted in increased recruitment of macrophages, which can serve as a major source of pro-inflammatory cytokines, including TNF-α. Consequently, the aberrant lymphatic vessel growth observed in type 2 diabetes could account for the persistent inflammation that impairs wound healing (82). Further studies are necessary to determine whether IAL under diabetic conditions is also associated with other major complications, such as macroangiopathy, microangiopathy, and neuropathy.…”

The lymphatic vasculature revisited

“…To mention yet another field, the significance of the lymphatic vascular system in diabetes has also just begun to emerge (37). Finally, there are several diseases that are caused by genetic or neoplastic alterations of the LECs, including genetic forms of lymphedema, as presented in the Review by Miikka Vikkula (38).…”

Analysis of Long Non-Coding RNA Expression of Lymphatic Endothelial Cells in Response to Type 2 Diabetes

“…The detailed methods were described by Haemmerle M [17]. Briefly, skin samples (n = 4 in each group) were taken from the proximal region of amputated legs or abdominoplastic tissue, and care was taken to excise areas at maximal distance from inflammatory or ulcerous changes (15 cm).…”