Endothelin receptor antagonism ameliorates mast cell infiltration, vascular hypertrophy, and epidermal growth factor expression in experimental diabetes

Richard E. Gilbert, Jonathan R. Rumble, Zemin Cao, Alison J. Cox, Pauline Van Eeden, Terri J. Allen, Darren J. Kelly, Mark E. Cooper

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Abstract

Vascular hypertrophy, a feature of experimental and human diabetes, has been implicated in the pathogenesis of the microvascular and macrovascular complications of the disease. In the present study, we sought to examine the role of endogenous endothelin and its relation to vascular growth factors in the mediation of vascular hypertrophy in experimental diabetes and to examine the contribution of mast cells to this process. Vessel morphology, endothelin, growth factor gene expression, and matrix deposition were studied in the mesenteric arteries of control and streptozotocin-induced diabetic Sprague-Dawley rats treated with or without the dual endothelin(A/B) receptor antagonist bosentan (100 mg · kg-1 · d-1) during a 3-week period. Compared with control animals, diabetic animals had significant increases in vessel weight, wall-to-lumen ratio, mast cell infiltration, extracellular matrix deposition, and gene expression of epidermal growth factor (EGF) and transforming growth factor-β1. In diabetic, but not control, vessels, not only were EGF mRNA and endothelin present in endothelial cells, but also their expression was observed in adventitial mast cells. Immunoreactive endothelin was present in the media of mesenteric vessels of diabetic, but not control, animals. Bosentan treatment significantly reduced mesenteric weight, wall-to-lumen ratio, mast cell infiltration, matrix deposition, and EGF mRNA but did not prevent the overexpression of transforming growth factor-β1 mRNA in diabetic rats. These findings suggest that endogenous endothelin and EGF may play a role in diabetes-induced vascular hypertrophy and that mast cells may be pathogenetically involved in this process.

Original languageEnglish
Pages (from-to)158-165
Number of pages8
JournalCirculation Research
Volume86
Issue number2
DOIs
Publication statusPublished - 1 Jan 2000
Externally publishedYes

Keywords

  • Diabetes
  • Endothelin
  • Growth factor
  • Mast cell
  • Vasculature

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