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

  1. Brigitte Hantusch1
  1. 1Clinical Institute of Pathology, Medical University of Vienna, Vienna, Austria
  2. 2Department of Internal Medicine, Division of Rheumatology, Medical University of Vienna, Vienna, Austria
  3. 3Section for Science of Complex Systems, Medical University of Vienna, Vienna, Austria
  4. 4Division of Vascular Surgery, Department of Surgery, Medical University of Vienna, Vienna, Austria
  1. Corresponding author: Brigitte Hantusch, brigitte.hantusch{at}meduniwien.ac.at.

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.

Footnotes

  • Received June 22, 2012.
  • Accepted February 9, 2013.

Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.

| Table of Contents

This Article

  1. Diabetes vol. 62 no. 7 2509-2529
  1. Supplementary Data
  2. All Versions of this Article:
    1. db12-0844v1
    2. 62/7/2509 most recent