In utero exposure to maternal diabetes exacerbates dietary sodium intake-induced endothelial dysfunction by activating cyclooxygenase 2-derived proteinoids.

Prenatal exposure to maternal diabetes has been identified as a cardiovascular risk factor. It is unclear if offspring exposed to diabetes in utero manifest a worse vascular outcome to a high salt (HS) diet. To test the hypothesis that in utero exposure to maternal diabetes facilitates salt-induced vascular dysfunction, we treated adult male wild-type offspring (DM_Exp, 6-months-old) of diabetic Ins2+/C96Y mice (Akita mice) with HS (8% sodium chloride, 10-days) and analyzed endothelial function via wire myograph and cyclooxygenase (COX)-derived prostanoids pathway by ELISA, qPCR, and immunochemistry. At basal condition, DM_Exp mice did not manifest any vascular dysfunction, remodeling, or inflammation. However, HS increased the aortic contractility to phenylephrine and induced endothelial dysfunction (analyzed by acetylcholine-induced endothelium-dependent relaxation), vascular hydrogen peroxide production, COX2 expression, and prostaglandin E2 (PGE2) overproduction. Interestingly, ex vivo antioxidant treatment (tempol, 100µM) or COX1/2 (indomethacin, 10µM) or COX2 (NS398, 10µM) inhibitors improved or reverted the endothelial dysfunction in DM_Exp treated with HS. Finally, DM_Exp mice treated with HS exhibited greater circulating cytokines and chemokines accompanied by vascular inflammation. In summary, our findings indicate that prenatal exposure to maternal diabetes predisposes to high-salt (HS)-induced vascular dysfunction, primarily through the induction of oxidative stress and the generation of COX2-derived PGE2. Therefore, in utero exposure to maternal diabetes operates as a cardiovascular risk factor in adulthood.