title: 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.
authors: Clinical Institute of Pathology, Medical University of Vienna, Vienna, Austria.
authors: Monika
authors: M
authors: Haemmerle
authors: Thomas
authors: T
authors: Keller
authors: Gerda
authors: G
authors: Egger
authors: Helga
authors: H
authors: Schachner
authors: Carl Walter
authors: CW
authors: Steiner
authors: Dejan
authors: D
authors: Stokic
authors: Christoph
authors: C
authors: Neumayer
authors: Markus K
authors: MK
authors: Brown
authors: Dontscho
authors: D
authors: Kerjaschki
authors: Brigitte
authors: B
authors: Hantusch
mesh_terms: D000328:Adult; D054357:Chemokine CXCL10 / Q000235:genetics / Q000378:metabolism; D020405:Dermis / Q000378:metabolism* / Q000473:pathology; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D042783:Endothelial Cells / Q000378:metabolism* / Q000473:pathology; D015870:Gene Expression; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D042601:Lymphatic Vessels / Q000378:metabolism* / Q000473:pathology; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D059467:Transcriptome; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
chemical_list: D054357:Chemokine CXCL10; D014409:Tumor Necrosis Factor-alpha