Glycemic control prevents microvascular remodeling and increased tone in Type 2 diabetes: Link to endothelin-1

Kamakshi Sachidanandam, Jim R. Hutchinson, Mostafa M. Elgebaly, Erin M. Mezzetti, Anne M. Dorrance, Kouros Motamed, Adviye Ergul

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Abstract

Medial thickening and vascular hypertrophy of resistance arteries can lead to cardiovascular complications associated with diabetes. While previous studies have established a role of Type 1 diabetes in vascular remodeling, we recently extended these observations to Type 2 diabetes and reported increased collagen deposition due to alterations in matrix metalloproteinase expression and activity in mesenteric resistance arteries. These studies also showed that remodeling response was mediated by endothelin-1 (ET-1) via activation of ETA receptors, whereas blockade of ETB receptors exacerbated the remodeling. However, the effectiveness of glycemic control strategies in preventing these vascular changes, including activation of the ET system still remained unclear. Also, very little is known about whether and to what extent reorganization of the extracellular matrix (ECM) affects vascular compliance and vasomotor tone. Accordingly, this study assessed structural remodeling of mesenteric microvessels, vascular compliance, and myogenic tone, as well as the role of matrix metalloproteinases (MMP) in mediating these processes. Spontaneously diabetic, non-obese Goto-Kakizaki (GK) rats, a model for Type 2 diabetes, and normoglycemic Wistar rats were used for the studies. A subset of GK rats were administered metformin to achieve euglycemia. Glycemic control normalized the increased media-to-lumen ratios (M/L) and myogenic tone seen in diabetes, as well as normalizing plasma ET-1 levels and mesenteric ETA receptor expression. There was increased collagen synthesis in diabetes paralleled by decreased collagenase MMP-13 activity, while glycemic control attenuated the process. These findings and our previous study taken together suggest that hyperglycemia-mediated activation of ET-1 and ET A receptors alter vascular structure and mechanics in Type 2 diabetes.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Regulatory Integrative and Comparative Physiology
Volume296
Issue number4
DOIs
StatePublished - Apr 1 2009

Fingerprint

Endothelin-1
Type 2 Diabetes Mellitus
Blood Vessels
Matrix Metalloproteinases
Compliance
Collagen
Matrix Metalloproteinase 13
Mesenteric Arteries
Metformin
Collagenases
Microvessels
Mechanics
Type 1 Diabetes Mellitus
Hyperglycemia
Vascular Resistance
Hypertrophy
Extracellular Matrix
Wistar Rats
Arteries

Keywords

  • Endothelin receptors
  • Extracellular matrix
  • Glycemic control
  • Vascular compliance
  • Vascular remodeling

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)

Cite this

Glycemic control prevents microvascular remodeling and increased tone in Type 2 diabetes : Link to endothelin-1. / Sachidanandam, Kamakshi; Hutchinson, Jim R.; Elgebaly, Mostafa M.; Mezzetti, Erin M.; Dorrance, Anne M.; Motamed, Kouros; Ergul, Adviye.

In: American Journal of Physiology - Regulatory Integrative and Comparative Physiology, Vol. 296, No. 4, 01.04.2009.

Research output: Contribution to journalArticle

Sachidanandam, Kamakshi ; Hutchinson, Jim R. ; Elgebaly, Mostafa M. ; Mezzetti, Erin M. ; Dorrance, Anne M. ; Motamed, Kouros ; Ergul, Adviye. / Glycemic control prevents microvascular remodeling and increased tone in Type 2 diabetes : Link to endothelin-1. In: American Journal of Physiology - Regulatory Integrative and Comparative Physiology. 2009 ; Vol. 296, No. 4.
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