Review 10.1586/14779072.4.2.227 © 2006 Future Drugs Ltd ISSN 1477-9072 227 www.future-drugs.com Nutrient- restricted fetus and the cardio–renal connection in hypertensive offspring Jeffrey S Gilbert, Laura A Cox, Graham Mitchell and Mark J Nijland † † Author for correspondence Department of Obstetrics and Gynecology and Center for Pregnancy and Newborn Research, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA; and Center for the Study of Fetal Programming, University of Wyoming, Laramie, WY 82071, USA Tel.: +1 210 567 5055 Fax: +1 210 567 3406 nijland@cybersci.com KEYWORDS: angiotensin, blood pressure, fetus, gestation, heart, kidney, nephron number, pregnancy, vascular dysfunction A suboptimal intrauterine environment has a number of deleterious effects on fetal development and postpartum health outcomes. Epidemiological studies on several human populations have linked socioeconomic status and low birth weight to an increased incidence of diseases such as hypertension, diabetes, obesity and cardiovascular disease. A growing number of experimental studies in a variety of animal models demonstrate that maternal stressors, such as nutrition and reduced uterine perfusion, affect the intrauterine milieu and result in increased blood pressure in offspring. Several mechanisms appear to contribute to hypertension, including vascular dysfunction and increased peripheral resistance, altered cardio–renal structure and alterations in cardio–renal function. Although many studies have characterized models of developmentally generated hypertension, few have begun to seek therapeutic modalities to ameliorate its incidence. This review discusses recent work that refines hypotheses linking a suboptimal intrauterine environment to cardiovascular and renal phenotypes that have increased susceptibility to cardiovascular disease and hypertension. Expert Rev. Cardiovasc. Ther. 4(2), 227–238 (2006) Gestation is a considerable physiological stress. Adaptation to this stress requires synchronized adjustments to maternal physiology. T he proper regulation of energy, fluid and electro- lyte balance is critical to the maintenance of maternal homeostasis, while at the same time, the needs of a rapidly growing conceptus must be met. When homeostasis fails, a suboptimal intrauterine environment results. Well-recognized causes of a suboptimal intra- uterine environment are inadequate maternal nutrition, hyperemesis gravidarum and placen- tal insufficiency caused by hypertension of pregnancy, all of which are known to impair fetal development [1–5]. A marker of suboptimal uterine environment often used is low birth weight, but it is now acknowledged that weight at birth is an inadequate measure. T his is par- ticularly true when the insult occurs during early-to-mid gestation and can be ameliorated during the balance of the pregnancy [6,7]. More sensitive markers of fetal dysplasia (e.g., growth restriction) are needed, particularly markers of changes in critical organs such as the heart and kidneys. T his article reviews and discusses recent work that defines what such markers might be, with respect to car- dio–renal development, and also reviews work that refines hypotheses linking a suboptimal intrauterine environment to the generation of cardiovascular and renal phenotypes, which are associated with increased susceptibility to cardiovascular disease and hypertension in later life. Developmental origins of health & disease T he developmental origins of health and dis- ease (DOHaD) hypothesis, also known as fetal programming or the Barker hypothesis, is derived from observed long-term effects for adult health in persons of low birth weight [8,9]. Although Barker has been widely credited with the first articulation of this hypothesis, earlier studies in northern Europe hinted at similar relationships between early life experience and adult health [10,11]. In addition, previous authors had evaluated the same phenomenon from a CONTENTS Compromised fetal environment: how does it happen? Factors contributing to the developmental origins of hypertension Gender differences in programmed hypertension Expert commentary Five-year view Key issues References Affiliations For reprint orders, please contact reprints@future-drugs.com