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Abstract-Epidemiological studies suggest that maternal cigarette smoking is associated with an increased risk of elevated blood pressure (BP) in postnatal life. The present study tested the hypothesis that prenatal nicotine exposure causes an increase in BP response to angiotensin II (Ang II) in adult offspring. Nicotine was administered to pregnant rats via subcutaneous osmotic minipumps throughout the gestation. BP and vascular responses to Ang II were measured in 5-month-old adult offspring. Prenatal nicotine had no effect on baseline BP but significantly increased Ang II-stimulated BP in male but not female offspring. The baroreflex sensitivity was significantly decreased in both male and female offspring. Prenatal nicotine significantly increased arterial media thickness in male but not female offspring.In male offspring, nicotine exposure significantly increased Ang II-induced contractions of aortas and mesenteric arteries. These responses were not affected by inhibition of endothelial NO synthase activity. Losartan blocked Ang II-induced contractions in both control and nicotine-treated animals. In contrast, PD123319 had no effect on Ang II-induced contractions in control but inhibited them in nicotine-treated animals. Nicotine significantly increased Ang II type 1 receptor but decreased Ang II type 2 receptor protein levels, resulting in a significant increase in the ratio of Ang II type 1 receptor/Ang II type 2 receptor in the aorta. Furthermore, the increased contractions of mesenteric arteries were mediated by increases in intracellular Ca 2ϩ concentrations and Ca 2ϩ sensitivity. These results suggest that prenatal nicotine exposure alters vascular function via changes in Ang II receptor-mediated signaling pathways in adult offspring in a gender-specific manner, which may lead to an increased risk of hypertension in male offspring. Key Words: nicotine Ⅲ fetal programming Ⅲ gender Ⅲ angiotensin II Ⅲ vascular contractility M aternal cigarette smoking probably is the single most widespread prenatal insult in the world. Recent epidemiological studies have demonstrated that in utero exposure to maternal smoking is associated with elevated blood pressure (BP) and/or cardiovascular disease in offspring later in life. 1,2 As one of the major components in cigarette smoking, nicotine is likely to contribute to the developmental programming of cardiovascular disorders. Nicotine readily crosses the placenta, and maternal cigarette smoking produces higher nicotine concentrations in fetal circulation than that experienced by the mother. 3,4 In the developing fetus, chronic nicotine exposure resulted in permanent changes in nicotinic receptors and alterations in the activity of the central and peripheral nervous systems. 5 Our recent studies in the rat have demonstrated that fetal nicotine exposure causes reprogramming of vascular reactivity and produces genderdependent alterations in both ␣ 1 -adrenoceptor-mediated contractions and endothelial NO synthase (eNOS) activity of arteries in adult offspring. 6 In additi...

We have examined age-related changes in segments of common carotid (Com), basilar (Bas), posterior communicating (PC), and middle cerebral (MC) arteries taken from 14 near-term fetal lambs, 62 newborn lambs 3-7 days old, and 42 adult nonpregnant sheep. Transition from fetal to newborn life was associated with a decreased water content in all arteries ranging from 0.6% (Com) to 2.3% (Bas), no change in the relative content of cellular protein, an increase in wall thickness ranging from 4% (MC) to 26% (Com), an increase in maximum contractile tension ranging from 18% (MC) to 82% (Com), an increase in stiffness, an increase in the maximum active stress ranging from 6% (Bas) to 43% (Com), a decrease in the amine-to-potassium ratio (calculated as the maximum response to 10 microM serotonin with 20 microM histamine divided by the maximum response to 122 mM K+) ranging from 8% (Bas) to 51% (Com), and a decrease in the norepinephrine-to-potassium ratio ranging from 2.1% (Bas) to 56% (Com). Thus developmental changes associated with the transition from fetal to newborn life were much more pronounced in the larger, more proximal Com than in the smaller, more distal cerebral arteries, suggesting that, at term, the cerebral arteries are more mature both functionally and structurally than the Com arteries. Similarly, the transition from newborn to adult life was associated with much greater changes in Com characteristics than with those of the cerebral arteries. These studies demonstrate that the effects of aging vary considerably along the cerebrovascular tree and that conclusions based on developmental studies of large systemic arteries cannot be freely extrapolated to the smaller arteries of the circle of Willis.

In 2002, the American College of Obstetricians and Gynecologists published exercise guidelines for pregnancy, which suggested that in the absence of medical or obstetric complications, 30 minutes or more of moderate exercise a day on most, if not all, days of the week is recommended for pregnant women. However, these guidelines did not define 'moderate intensity' or the specific amount of weekly caloric expenditure from physical activity required. Recent research has determined that increasing physical activity energy expenditure to a minimum of 16 metabolic equivalent task (MET) hours per week, or preferably 28 MET hours per week, and increasing exercise intensity to ≥60% of heart rate reserve during pregnancy, reduces the risk of gestational diabetes mellitus and perhaps hypertensive disorders of pregnancy (i.e. gestational hypertension and pre-eclampsia) compared with less vigorous exercise. To achieve the target expenditure of 28 MET hours per week, one could walk at 3.2 km per hour for 11.2 hours per week (2.5 METs, light intensity), or preferably exercise on a stationary bicycle for 4.7 hours per week (∼6-7 METs, vigorous intensity). The more vigorous the exercise, the less total time of exercise is required per week, resulting in ≥60% reduction in total exercise time compared with light intensity exercise. Light muscle strengthening performed over the second and third trimester of pregnancy has minimal effects on a newborn infant's body size and overall health. On the basis of this and other information, updated recommendations for exercise in pregnancy are suggested.

For the developing fetal brain RAS, MLPD leads to significant alterations in the mRNA and protein expression, with changes in DNA methylation and miRNA, key regulators of hypertension in adults.