Sex differences in the fetal programming of hypertension

Abstract

Background: Numerous clinical and experimental studies support the hypothesis that the intrauterine environment is an important determinant of cardiovascular disease and hypertension.

Objective: This review examined the mechanisms linking an adverse fetal environment and increased risk for chronic disease in adulthood with an emphasis on gender differences and the role of sex hormones in mediating sexual dimorphism in response to a suboptimal fetal environment.

Methods: This review focuses on current findings from the PubMed database regarding animal models of fetal programming of hypertension, sex differences in phenotypic outcomes, and potential mechanisms in offspring of mothers exposed to an adverse insult during gestation. For the years 1988 to 2007, the database was searched using the following terms: fetal programming, intrauterine growth restriction, low birth weight, sex differences, estradiol, testosterone, high blood pressure, and hypertension.

Results: The mechanisms involved in the fetal programming of adult disease are multifactorial and include alterations in the regulatory systems affecting the long-tterm control of arterial pressure. Sex differences have been observed in animal models of fetal programming, and recent studies suggest that sex hormones may modulate activity of regulatory systems, leading to a lower incidence of hypertension and vascular dysfunction in females compared with males.

Conclusions: Animal models of fetal programming provide critical support for the inverse relationship between birth weight and blood pressure. Experimental models demonstrate that sex differences are observed in the pathophysiologic response to an adverse fetal environment. A role for sex hormone involvement is strongly suggested,with modulation of the renin-angiotensin system as a possible mechanism.

Figure 1

Castration abolishes hypertension in male intrauterine growth restricted (IUGR) offspring. Mean arterial pressure was measured by radio telemetry from 12 to 16 weeks of age in conscious, free moving animals that underwent either sham (intact) or castration (CTX) at 10 weeks of age. * P<0.05 vs. Control intact, † P<0.05 vs. IUGR intact. Used with permission from reference ; Am J Physiol Regul Integr Comp Physiol. 2007;292(2):R758−63.

Figure 2

Ovariectomy induces significant increases in mean arterial pressure in adult female intrauterine growth restricted (IUGR) offspring. Mean arterial pressure was measured by radio telemetry from 12 to 16 weeks of age in animals that underwent either sham (intact) or ovariectomy (OVX) at 10 weeks of age. *P<0.01 vs. IUGR intact. Used with permission from reference ; Hypertension 2007; 50:679−685.