Epigenetic Modification of the Renin-Angiotensin System in the Fetal Programming of Hypertension

Abstract

Abstract-Hypertension is a major risk factor for cardiovascular and cerebrovascular disease. Lifelong environmental factors (eg, salt intake, obesity, alcohol) and genetic factors clearly contribute to the development of hypertension, but it has also been established that stress in utero may program the later development of the disease. This phenomenon, known as fetal programming can be modeled in a range of experimental animal models. In maternal low protein diet rat models of programming, administration of angiotensin converting enzyme inhibitors or angiotensin receptor antagonists in early life can prevent development of hypertension, thus implicating the renin-angiotensin system in this process. Here we show that in this model, expression of the AT 1b angiotensin receptor gene in the adrenal gland is upregulated by the first week of life resulting in increased receptor protein expression consistent with the increased adrenal angiotensin responsiveness observed by others. Furthermore, we show that the proximal promoter of the AT 1b gene in the adrenal is significantly undermethylated, and that in vitro, AT 1b gene expression is highly dependent on promoter methylation. These data suggest a link between fetal insults to epigenetic modification of genes and the resultant alteration of gene expression in adult life leading ultimately to the development of hypertension. It seems highly probable that similar influences may be involved in the development of human hypertension. (Circ Res. 2007;100:520-526.)

A Life Course Perspective on Body Size and Cardio-metabolic Health

“…While an environmental exposure may influence body size in the short term, these "epigenetic" changes can have long lasting effects on disease risk. Maternal protein restriction might lead to smaller offspring and reduce methylation (and therefore enhance expression) of the angiotensinogen receptor gene in the offspring adrenal gland, thereby leading to high blood pressure, for example (Bogdarina et al 2007;Woodall et al 1996). Such epigenetic changes can occur from conception onward but, like the other anatomical and physiological pathways, are most sensitive to the environment during specific stages of the life course.…”

Developmental and epigenetic pathways to obesity: an evolutionary-developmental perspective

“…18 But developmental plasticity operates within the normative range of developmental environments, and there is growing evidence that there is extensive and specific regulation of non-imprinted genes in such environmentally regulated plasticity. [19][20][21][22] As developmental plasticity is basically an adaptive process, it seems more likely that it will be non-parentally imprinted genes that will be primarily involved in developmental pathways to obesity.…”

Maternal Undernutrition Induces the Expression of Hypoxia-Related Genes in the Fetal Brain

“…Hypertension is one of the major factors of cerebrovascular and cardiovascular disease (He and MacGregor 2003). In fact, maternal undernutrition during pregnancy increases risks for cerebrovascular and cardiovascular disease on the fetal adulthood, which has been demonstrated in epidemiological (Barker et al 1990) and animal studies (Otani et al 2004;Bogdarina et al 2007).…”