Stimulation of autophagy improves vascular function in the mesenteric arteries of type 2 diabetic mice

Exp Physiol. 2020 Jan;105(1):192-200. doi: 10.1113/EP087737. Epub 2019 Dec 19.

Abstract

New findings: What is the central question of this study? What is the role of autophagy in vascular dysfunction in type 2 diabetes? What is the main finding and its importance? Autophagy is decreased in the mesenteric arteries of type 2 diabetic mice, and stimulation of autophagy using rapamycin and trehalose improves vascular function, which is associated with normalization of myogenic response and endothelium-dependent relaxation.

Abstract: Vascular dysfunction is a major complication in type 2 diabetes (T2D). It has been suggested that dysregulation of autophagy is associated with various cardiovascular diseases. However, the relationship between autophagy and vascular dysfunction in T2D remains unclear. Thus, we examined whether reduced autophagy is involved in vascular dysfunction and whether stimulation of autophagy could improve vascular function in diabetes. Ten- to twelve-week-old male type 2 diabetic (db- /db- ) mice and their control (db- /db+ ) mice were treated with rapamycin or trehalose. Mesenteric arteries (MAs) were mounted for arteriography and their diameter was measured. Western blot analysis and immunofluorescence staining were assessed. Myogenic response (MR) was significantly increased, whereas endothelium-dependent relaxation (EDR) was significantly attenuated in the MAs of diabetic mice. These results were associated with increased expression of LC3II, p62 and beclin-1 in diabetic mice. Treatment with autophagy stimulators significantly reduced the potentiation of MR and improved EDR in the diabetic mice. Furthermore, autophagy stimulation normalized expression of LC3II, p62 and beclin-1 in the diabetic mice. In addition, phosphorylation level of endothelial nitric oxide synthase was decreased in diabetic mice and was restored by rapamycin and trehalose. T2D impairs vascular function by dysregulated autophagy. Therefore, autophagy could be a potential target for overcoming diabetic microvascular complications.

Keywords: autophagy; endothelium-dependent relaxation; mesenteric artery; myogenic response; type 2 diabetes; vascular dysfunction.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autophagy*
  • Diabetes Mellitus, Experimental / physiopathology
  • Diabetes Mellitus, Type 2 / physiopathology*
  • Endothelium, Vascular / drug effects*
  • Endothelium, Vascular / physiopathology
  • Male
  • Mesenteric Arteries / drug effects*
  • Mesenteric Arteries / physiopathology
  • Mice
  • Sirolimus / pharmacology
  • Trehalose / pharmacology

Substances

  • Trehalose
  • Sirolimus