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The structure and endothelial function of small arteries: mechanisms in an experimental model of type 2 diabetes

Hus Chen


Small artery remodeling and endothelial dysfunction are predictors of type 2 diabetes. In this PhD thesis, the effect of cystamine, a substrate and active-site inhibitor of tissue transglutaminase, on the remodeling of rat mesenteric small arteries was investigated (manuscript I) ; the effect of sulfaphenazole, a specific cytochrome P450 2C9 inhibitor, was investigated on acetylcholine-induced relaxation of mesenteric small arteries in db/db mice (manuscript II) ; a role of gender-specific cyclooxygenase-derived prostanoids for acetylcholine-induced relaxation of mouse mesenteric small arteries was found (manuscript III).Our findings showed:

1. Cystamine and amlodipine inhibited phenylephrine vasoconstriction in a concentration-dependent manner. Addition of cystamine potentiated the effect induced by amlodipine. Furthermore, cystamine treatment significantly blocked the inward remodeling stimulated with endothelin-1. Amlodipine alone caused outward remodeling and the addition of cystamine did not have any further significant effect on this. Calcium-independent and decreased extracellular tTG activity was observed during vascular remodeling.

2. Sulfaphenazole treatment in vivo and vitro significantly improved the impaired relaxation to acetylcholine in mesenteric small arteries of db/db mice. The intracellular calcium transients in endothelial cells induced by acetylcholine were markedly lower in db/db arteries compared to db/+ mice. Acute sulfaphenazole treatment significantly enhanced the percentage of responding endothelial cells. Intracellular reactive oxygen species were more pronounced in arteries from diabetic mice, this difference disappeared after sulfaphenazole incubation.

3. Acetylcholine induced smaller vasodilations in mesenteric small arteries from male db/+ mice than females. Relaxant responses in the presence of L-NAME and indomethacin were significantly increased compared to those in the presence of only L-NAME in males. This was not observed in females. In arteries of male wild type mice, relaxations in the presence of L-NAME and indomethacin or SQ29,548 were significantly increased compared to those in the presence of only L-NAME. In contrast, there was no effect of COX inhibition in females.Taken together these observations suggest a potential role of cystamine and sulfaphenazole in the treatment of cardiovascular diseases, in particular diabetes. Inhibition of the bioavailability and/or effect of gender-specific prostanoids may be promising therapeutic targets to prevent cardiovascular diseases in males.