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Review
. 2008 Dec;295(6):R1941-52.
doi: 10.1152/ajpregu.90724.2008. Epub 2008 Oct 29.

Sex differences in the developmental origins of hypertension and cardiorenal disease

Jeffrey S Gilbert  1 , Mark J Nijland
Affiliations
Review

Sex differences in the developmental origins of hypertension and cardiorenal disease

Jeffrey S Gilbert et al. Am J Physiol Regul Integr Comp Physiol. 2008 Dec.

Abstract

The "developmental origins of health and disease" (DOHAD) hypothesis derives from clinical observations, indicating long-term health consequences for persons of low birth weight. There is growing evidence, primarily from animal studies, that supports the idea that processes put in motion during development that contribute to DOHAD do not necessarily reflect as significantly compromised growth and altered birth weight. Throughout the body of work investigating the DOHAD hypothesis, several themes have emerged; the importance of the placenta, the presence of critical periods of vulnerability, the involvement of the kidney in programmed hypertension, the presence of sex differences in the progression and development of adult diseases. Despite compelling findings in recent studies, much remains unclear regarding the impact of biological sex in the progression of human diseases, in general, and in the mechanisms underlying developmentally programmed responses, in particular. Although the contribution of biological sex to DOHAD is increasingly recognized, it also appears that it may exert distinctly different influences during fetal and adult life. The mechanisms by which biological sex contributes to these processes remains nebulous at present; nevertheless, several intriguing mechanistic candidates have been proposed ranging from differences in the amounts of sex hormones (e.g., estrogens, androgens) to recently described sexual dimorphism in the transcriptome of a variety of mammalian tissues. Recognizing the influences of biological sex or sex hormones on DOHAD uniquely situates research in this area to provide significant insights into the development and progression of many diseases, recent examples of which are the subject of this review.

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Figures

Fig. 1.
Fig. 1.
Overview of pathways by which various maternal and fetal stressors may interact with sex and sex hormones to result in adult hypertension. Environmental factors, such as undernutrition and overnutrition and impaired placental perfusion, may influence epigenetic regulatory mechanisms in addition to restricting fetal growth and development. Although alterations in the fetal ANG II signaling are common to most models of developmental programming, dysregulation of PG via cyclooxygenase-2 (COX2) has recently been reported. Biological sex of the fetus influences the response to these factors and may determine the extent of suppression or activation of the ANG II or PG pathways. In addition to disruption of renal nephro- and tubulo-genesis during fetal life, programmed alterations in sex hormones contribute to cardiorenal dysfunction and result in adult hypertension.
Fig. 2.
Fig. 2.
Mechanisms underlying sexual dimorphism in developmental programming of hypertension. The mechanisms underlying the processes of developmental programming can be broadly grouped into epigenetic (and possibly nutrigenetic) and endocrine/nervous system categories. Several pathways, including the RAS, prostaglandins via cyclooxygenase-2 (COX2), glucocorticoids (GC), and sex steroids (androgens and estrogens) have been identified as playing a mechanistic role in the developmentally programmed hypertension. Although a large body of work clearly supports the importance of endocrine pathways in developmental programming of cardiorenal disease, the epigenetic mechanisms are poorly defined. A working hypothesis is that epigenetic alterations directly induce changes in gene expression and ultimately phenotype; whereas endocrine/nervous system changes directly influence gene expression and/or physiological function. Alterations in gene expression and organogenesis contribute to functional deficits and ultimately disease states such as hypertension, cardiorenal disease and the metabolic syndrome. Although the manner in which epigenetic phenomena contribute to the programming of cardiorenal dysfunction remains unclear, the role of sex steroids has been studied extensively. While sex steroids appear to interact with the programmed phenotype of the offspring and contribute to cardiorenal dysfunction and hypertension, the altered levels of those hormones may be a result of epigenetic alterations. Black arrows indicate relationships supported by experimental evidence; gray arrows indicate relationships that are currently in question or are suggested but as yet unproven.
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