Journal
BRITISH JOURNAL OF PHARMACOLOGY
Volume 166, Issue 7, Pages 2198-2208Publisher
WILEY
DOI: 10.1111/j.1476-5381.2012.01945.x
Keywords
diabetes; hypertension; fetal programming; endothelial dysfunction; cyclooxygenase; prostanoids; insulin resistance
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Funding
- Fundacao de Amparo a Ciencia e Tecnologia do Estado de Pernambuco (FACEPE)
- PIBIC/UFPE
- Conselho Nacional de Desenvolvimento Cientifico e Tecnologico
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BACKGROUND AND PURPOSE The present study was designed to determine how diabetes in pregnancy affects vascular function in their offspring, the influence of age and whether COX activation is involved in this effect. EXPERIMENTAL APPROACH Relaxation responses to ACh were analysed in mesenteric resistance arteries from the offspring of control rats (O-CR) and those of diabetic rats (O-DR) at 3, 6 and 12 months of age. TxB2, PGE2 and PGF2a release were determined by enzyme immunoassay. COX-1 and COX-2 expression were measured by Western blot analysis. KEY RESULTS O-DR developed hypertension from 6 months of age compared with O-CR. In O-DR, relaxation responses to ACh were impaired in all ages studied and were restored by COX-2 inhibition. TP receptor blockade (SQ29548) restored ACh relaxation in arteries from 3-month-old O-DR while TP and EP receptor blockade (SQ29548 + AH6809) was required to restore it in 6-month-old O-DR. In 12-month-old O-DR, ACh relaxation was restored when TP, EP and FP receptors were blocked (SQ29548 + AH6809 + AL8810). ACh-stimulated TxB2 was higher in all O-DR. ACh-stimulated PGE2 release was increased in arteries from 6- and 12-month-old O-DR, whereas PGF2a was increased only in 12-month-old O-DR. COX-2, but not COX-1, expression was higher in O-DR than O-CR. CONCLUSIONS AND IMPLICATIONS The results indicate an age-dependent up-regulation of COX-2 coupled to an enhanced formation of vasoconstrictor prostanoids in resistance arteries from O-DR. This effect plays a key role in the pathogenesis of endothelial dysfunction, which in turn could contribute to the progression of vascular dysfunction in these rats.
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