Developmental origins of cardiovascular disease: alterations in gestational hypertension and stroke outcome in adult offspring

Abstract

The developmental origins of health and disease (DOHaD), originally defined by Dr. David Barker, recognizes that in addition to adverse exposures in adulthood, influences during early stages of development contribute significantly to disease risk later in life. This suggests additional target periods for intervention across the course of life that will assist in reducing the global burden of disease. The development of hypertensive disorders of pregnancy (HDP) or other pregnancy-related syndromes, negatively affects both the maternal and fetal physiological systems predisposing mothers and infants to increased incidence of cardiovascular disease (CVD). We hypothesize that gestational hypertension, a mild form of HDP, impacts maternal cardiac remodeling during pregnancy and the response of offspring to a cardiovascular disease stress, such as acute ischemic stroke in adulthood. The established atrial natriuretic peptide gene-disrupted (ANP−/−) mouse model was utilized in this thesis to investigate the influence of chronic and gestational hypertension on pregnancy-induced cardiac alterations in addition to cerebrovascular response to stroke. Objectively, we sought to characterize novel methods to investigate the effects of fetal-programming on ischemic stroke and provide experimental evidence to correspond with currently published epidemiological observations. Collectively, our data are the first to experimentally describe the long-term consequences of gestational hypertension and lack of maternal ANP on stroke outcome and cardiac remodeling over the course of pregnancy. During pregnancy, we have demonstrated the onset and regression of pregnancy-induced cardiac hypertrophy as well as the local cardiac mRNA expression of the renin-angiotensin and natriuretic peptide systems (RAS and NPS, respectively). We have additionally shown up regulation of the RAS late in pregnancy while the NPS was up regulated post partum. Herein, we have also demonstrated that although gestational hypertension did not adversely affect maternal cardiac remodeling over the course of pregnancy, gestational hypertension did significantly impact the cerebral response of offspring to focal ischemia by up regulating cerebral vasoactive systems implicated in ischemic stroke; namely the endothelin (ET) and nitric oxide synthase (NOS) systems.