Evidence for vasculoprotective effects of ETB receptors in resistance artery remodeling in diabetes

Kamakshi Sachidanandam, Vera Portik-Dobos, Alex K. Harris, Jim R. Hutchinson, Erin Muller, Maribeth H Johnson, Adviye Ergul

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Abstract

OBJECTIVE - Vascular remodeling, characterized by extracellular matrix deposition and increased media-to-lumen (M/l) ratio, contributes to the development of microvascular complications in diabetes. Matrix metalloproteinases (MMPs) play an important role in the regulation of extracellular matrix (ECM) turnover and vascular remodeling. Vasoactive factor endothelin (ET)-1 not only causes potent vasoconstriction but also exerts profibrotic and proliferative effects that change vessel architecture, which makes it a likely candidate for a key role in vascular complications of diabetes. Thus, this study investigated the regulation of MMP activity of resistance arteries under mild-to-moderate diabetes conditions, as seen in type 2 diabetes, and the relative role of ET receptors in this process. RESEARCH DESIGN AND METHODS - Vessel structure, MMP activity, and ECM proteins were assessed in control Wistar and diabetic Goto-Kakizaki (GK) rats treated with vehicle, ETA receptor antagonist atrasentan (5 mg · kg -1 · day-1), or ETB receptor antagonist A-192621 (15 mg · kg-1 · day-1) for 4 weeks. RESULTS - M/l ratio was increased in diabetes. Atrasentan prevented this increase, whereas A-192621 caused further thickening of the medial layer. Increased MMP-2 activity in diabetes was prevented by atrasentan treatment. Collagenase activity was significantly decreased in diabetes, and while ET A antagonism improved enzyme activity, ETB blockade further reduced collagenase levels. Accordingly, collagen deposition was augmented in GK rats, which was reversed by atrasentan but exacerbated with A-192621. CONCLUSIONS - ET-1 contributes to the remodeling of mesenteric resistance arteries in diabetes via activation of ETA receptors, and ETB receptors provide vasculoprotective effects.

Original languageEnglish (US)
Pages (from-to)2753-2758
Number of pages6
JournalDiabetes
Volume56
Issue number11
DOIs
StatePublished - Nov 1 2007

Fingerprint

A 192621
Arteries
Matrix Metalloproteinases
Endothelin-1
Collagenases
Diabetes Complications
Extracellular Matrix
Endothelin Receptors
Mesenteric Arteries
Extracellular Matrix Proteins
Matrix Metalloproteinase 2
Endothelins
Vasoconstriction
Type 2 Diabetes Mellitus
Blood Vessels
Research Design
Collagen
atrasentan
Enzymes
Vascular Remodeling

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Sachidanandam, K., Portik-Dobos, V., Harris, A. K., Hutchinson, J. R., Muller, E., Johnson, M. H., & Ergul, A. (2007). Evidence for vasculoprotective effects of ETB receptors in resistance artery remodeling in diabetes. Diabetes, 56(11), 2753-2758. https://doi.org/10.2337/db07-0426

Evidence for vasculoprotective effects of ETB receptors in resistance artery remodeling in diabetes. / Sachidanandam, Kamakshi; Portik-Dobos, Vera; Harris, Alex K.; Hutchinson, Jim R.; Muller, Erin; Johnson, Maribeth H; Ergul, Adviye.

In: Diabetes, Vol. 56, No. 11, 01.11.2007, p. 2753-2758.

Research output: Contribution to journalArticle

Sachidanandam, K, Portik-Dobos, V, Harris, AK, Hutchinson, JR, Muller, E, Johnson, MH & Ergul, A 2007, 'Evidence for vasculoprotective effects of ETB receptors in resistance artery remodeling in diabetes', Diabetes, vol. 56, no. 11, pp. 2753-2758. https://doi.org/10.2337/db07-0426
Sachidanandam K, Portik-Dobos V, Harris AK, Hutchinson JR, Muller E, Johnson MH et al. Evidence for vasculoprotective effects of ETB receptors in resistance artery remodeling in diabetes. Diabetes. 2007 Nov 1;56(11):2753-2758. https://doi.org/10.2337/db07-0426
Sachidanandam, Kamakshi ; Portik-Dobos, Vera ; Harris, Alex K. ; Hutchinson, Jim R. ; Muller, Erin ; Johnson, Maribeth H ; Ergul, Adviye. / Evidence for vasculoprotective effects of ETB receptors in resistance artery remodeling in diabetes. In: Diabetes. 2007 ; Vol. 56, No. 11. pp. 2753-2758.
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