What is the central question of this study? Hyperglycaemia during pregnancy induces vascular dysfunction and hypertension in male offspring. Given that female offspring from other fetal programming models are protected from the effects of fetal insult, the present study investigated whether there are sex differences in blood pressure and vascular function in hyperglycaemia-programmed offspring. What is the main finding and its importance? We demonstrated that hyperglycaemia in pregnant rats induced vascular dysfunction and hypertension only in male offspring. We found sex differences in oxidative stress and cyclooxygenase-2-derived prostanoid production that might underlie the vascular dysfunction. These differences, particularly in resistance arteries, may in part explain the absence of hypertension in female offspring born to hyperglycaemic dams. Exposure to maternal hyperglycaemia induces hypertension and vascular dysfunction in adult male offspring. Given that female offspring from several fetal programming models are protected from the effects of fetal insult, in this study we analysed possible differences relative to sex in blood pressure and vascular function in hyperglycaemia-programmed offspring. Hyperglycaemia was induced on day 7 of gestation (streptozotocin, 50 mg kg ). Blood pressure, acetylcholine and phenylephrine or noradrenaline responses were analysed in the aorta and mesenteric resistance arteries of 3-, 6- and 12-month-old male and female offspring. Thromboxane A release was analysed with commercial kits and superoxide anion (O ) production by dihydroethidium-emitted fluorescence. Male but not female offspring of hyperglycaemic dams (O-DR) had higher blood pressure than control animals (O-CR). Contraction in response to phenylephrine increased and relaxation in response to acetylcholine decreased only in the aorta from 12-month-old male O-DR and not in age-matched O-CR. Contractile and vasodilator responses were preserved in both the aorta and mesenteric resistance arteries from female O-DR of all ages. Pre-incubation with tempol, superoxide dismutase, indomethacin, NS-398, furegrelate or SQ29548 decreased contraction in response to phenylephrine and potentiated relaxation in response to acetylcholine in 12-month-old male O-DR aorta. In this artery, thromboxane A release and O generation were greater in O-DR than O-CR groups. In conclusion, exposure to hyperglycaemia in utero results in sex-specific and age-dependent hypertension. The fact that vascular function is preserved in female O-DR may in part explain the absence of hypertension in this group. In contrast, the peripheral artery dysfunction associated with increased cyclooxygenase-2-derived production of vasoconstrictor prostanoids could underlie the increased blood pressure in male O-DR.

Excessive production of reactive oxygen species via advanced glycation end products (AGEs) activates peroxisome proliferator-activated receptor gamma (PPARg) and the transcription factor nuclear factor-kB (NF-kB) in aortic vascular smooth muscle cells (VSMCs). Apocynin, a drug with an antioxidant effect, has also been proposed as a therapeutic agent for atherosclerotic disease.Objectives: This work investigates the effects of apocynin on the PPARg and NF-kB protein expression evoked by AGEs in cultured VSMCs from Goto-Kakisaki (GK) rats, a non-obese insulin model of both insulin resistance and type 2 diabetes. Materials and methods: VSMCs, isolated from aortas of GK and non-diabetic rats, were cultured. The expression of proteins was evaluated by Western blot. The blood glucose concentration was measured with a blood glucose test meter. The diabetes of GK rats was controlled by blood glucose and insulin determinations (non-fasting values). The serum insulin concentration was determined by radioimmunoassay.Results: In VSMCs from non-diabetic and GK rats, apocynin (1 and 10 mM) abolished the protein overexpression of NF-kB induced by glycated bovine serum albumin (AGEs-BSA) incubation. However, apocynin (1 and 10 mM) enhanced the expression of PPARg protein in the presence of AGEs-BSA (100 mg/mL) in VSMCs from non-diabetic, but not from GK rats. Conclusion: These findings suggest that apocynin decreases the incidence of alterations in VSMCs induced by AGEs through the reduction of NF-kB and may represent an attractive therapeutic approach to treat diabetes mellitus.

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