Sympathetic tone in the young: the mother weighs in.

The increasingly recognized notion that conditions during fetal life alter susceptibility to adult disease represents a prototype of how the environment can influence biological processes. Several conditions, including stress exposure, maternal nutrition, and environmental temperature, have been shown to affect the health of offspring. The fast-growing epidemic of obesity has witnessed mounting interest in the effect of maternal obesity on disease development in the offspring. In humans, epidemiological observations consistently noted the close relationship between maternal obesity and increased adiposity in the offspring. Offspring born to overweight or obese mothers were found to be at higher risk of developing greater weight gain or obesity during childhood, adolescence, or adulthood, suggesting that these disorders may have a developmental origin.1,2 These studies also raised the possibility of neonatal origins of the diseases commonly associated with obesity, including hypertension. Prospective cohort studies have demonstrated that maternal obesity promotes higher blood pressure in the offspring. Systolic blood pressure in the offspring was found to be, on average, 0.2 mm Hg higher for each 0.1 kg of excessive weight gained by the mother during the pregnancy.2 A causal relationship between exposure to obesity in the perinatal period and increased adiposity in the offspring may contribute to the current epidemic of obesity through a continuous intergenerational cycle (Figure). Studies across animal species have confirmed the epidemiological findings and shown that rodents or sheep gestated in obese dams develop greater adiposity and excess weight gain.1 These studies also demonstrated that inducing obesity in pregnant rodents predisposes the offspring to develop hypertension.3 This confirms a close relationship between maternal obesity and hypertension in the offspring. In the present issue of Hypertension, Samuelsson et al4 further explore and dissect the mechanisms involved in maternal obesity-induced hypertension in the offspring. Arterial pressure and autonomic function were assessed in the offspring born to obese rats as compared with lean controls. In line with their previous findings,3 rats born to obese dams exhibited higher arterial pressure. Strikingly, the increase in arterial pressure in the offspring occurred at early age (30 days), before the rats become obese, suggesting that the development of hypertension in the offspring of obese dams is independent of obesity. However, the increase in fat mass and plasma leptin in 90and 180-day–old offspring seems to enhance the arterial pressure increase, indicating that obesity may exacerbate the hypertension. Activity of the autonomic nervous system is a key determinant of blood pressure, and mounting evidence indicates that many forms of hypertension are initiated or maintained by autonomic dysfunction, including sympathetic overdrive.5 To test for potential defects in the autonomic function that may account for the increase in arterial pressure associated with the offspring of obese rats, Samuelsson et al4 performed several experiments. First, the arterial pressure response to restraint stress, which is thought to be mediated by the sympathetic nervous system, was analyzed. Restraint stress caused a greater increase in arterial pressure in the offspring of obese dams, a clue suggesting sympathetic overdrive in these animals. The sympathetic overdrive was confirmed by the demonstration of increased renal levels of catecholamines, an enhanced fall in arterial pressure after adrenergic receptor blockade, and an elevation in low-frequency oscillations of blood pressure. The enhanced sympathetic outflow in the offspring of the obese dams was associated with increased renal renin gene expression. The offspring of obese rats exhibited lower parasympathetic drive, as indicated by the spectral analysis of heart rate and impairment in baroreflex sensitivity. These alterations may contribute to maternal obesity-induced hypertension in the offspring. However, these changes in parasympathetic outflow, as well as baroreflex sensitivity, are observed only in the 90-days fatter offspring, indicating that these alterations may be attributable to obesity rather than fetal programming. These findings provide an important mechanistic insight into the developmental origins of hypertension by implicating heightened sympathetic drive. These studies also suggest that activity of the sympathetic nervous system is programmed during fetal life. This is supported by the demonstration that sympathetic overdrive occurs in nonobese young offspring. Additional evidence supporting fetal programming of the sympathetic nervous system derives from the studies demonstrating alterations in sympathetic tone in the offspring of animals exposed in their early life to various cues, such as temperature, litter size, and undernutrition.6 However, it is unclear how exposing fetuses to such different environments could lead to similar disease in the offspring. It is particularly striking that neonatal exposure to contrasting nutritional conditions, such as undernutrition and obesity (a state of overnutrition), produces comparable disorders in the offspring, including obesity and hypertension. It is possible that fetal exposure to various conditions leads to parallel The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association. From the Center on Functional Genomics of Hypertension, Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa. Correspondence to Kamal Rahmouni, Center on Functional Genomics of Hypertension, Department of Internal Medicine, University of Iowa Carver College of Medicine, 3135C MERF, Iowa City, IA 52242. E-mail [email protected] (Hypertension. 2010;55:00-00.) © 2009 American Heart Association, Inc.