Coronary microvascular dysfunction in a porcine model of early atherosclerosis and diabetes

M. van den Heuvel, O. Sorop, S.J. Koopmans, R.A. Dekker, R. de Vries, H.M.M. Beusekom, E.C. Eringa, D.J. Duncker, A.H.J. Danser, W.J. Giessen

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Detailed evaluation of coronary function early in diabetes mellitus (DM)-associated coronary artery disease (CAD) development is difficult in patients. Therefore, we investigated coronary conduit and small artery function in a preatherosclerotic DM porcine model with type 2 characteristics. Streptozotocin-induced DM pigs on a saturated fat/cholesterol (SFC) diet (SFC + DM) were compared with control pigs on SFC and standard (control) diets. SFC + DM pigs showed DM-associated metabolic alterations and early atherosclerosis development in the aorta. Endothelium-dependent vasodilation to bradykinin (BK), with or without blockade of nitric oxide (NO) synthase, endothelium-independent vasodilation to an exogenous NO-donor (S-nitroso-N-acetylpenicillamine), and vasoconstriction to endothelin (ET)-1 with blockade of receptor subtypes, were assessed in vitro. Small coronary arteries, but not conduit vessels, showed functional alterations including impaired BK-induced vasodilatation due to loss of NO (P <0.01 vs. SFC and control) and reduced vasoconstriction to ET-1 (P <0.01 vs. SFC and control), due to a decreased ETA receptor dominance. Other vasomotor responses were unaltered. In conclusion, this model demonstrates specific coronary microvascular alterations with regard to NO and ET-1 systems in the process of early atherosclerosis in DM. In particular, the altered ET-1 system correlated with hyperglycemia in atherogenic conditions, emphasizing the importance of this system in DM-associated CAD development.
Original languageEnglish
Pages (from-to)H85-H95
Number of pages11
JournalAmerican Journal of Physiology : Heart and Circulatory Physiology
Issue number1
Publication statusPublished - 2012


  • prediabetic metabolic syndrome
  • arterial resistance vessels
  • endothelial dysfunction
  • insulin-resistance
  • contractile responses
  • glucose-tolerance
  • s-nitrosothiols
  • risk-factors
  • blood-flow
  • mellitus

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    van den Heuvel, M., Sorop, O., Koopmans, S. J., Dekker, R. A., de Vries, R., Beusekom, H. M. M., Eringa, E. C., Duncker, D. J., Danser, A. H. J., & Giessen, W. J. (2012). Coronary microvascular dysfunction in a porcine model of early atherosclerosis and diabetes. American Journal of Physiology : Heart and Circulatory Physiology, 302(1), H85-H95.