Long-term consequences of hyper-androgenemic pregnancy on offspring
Polycystic ovary syndrome (PCOS), the most common endocrine disorder in young women, is characterized by hyperandrogenemia and metabolic dysfunction. In-utero, offspring of PCOS women are exposed to altered maternal hormonal environment and maternal obesity (for most of PCOS women). Offspring of PCOS women could also be subject to the transgenerational transmission of some of the PCOS traits. Offspring of PCOS women are commonly reported to have an abnormal birth weight (e.g. low birth weight (LBW)), that is associated with increased risk for cardiovascular (CV) disease (CVD) later in life. Yet, previous studies in PCOS offspring focused mainly on reproductive and metabolic health, with only few studies in children and teenagers addressing the consequences of PCOS pregnancy on CVD risk factors. Most importantly, there is no information on sex differences in CVD in adult PCOS offspring.
We use a well-characterized and clinically-relevant model of PCOS, the hyperandrogenemic female (HAF) rat, which mimics most characteristics of PCOS [e.g. insulin resistance, glucose intolerance, and increased blood pressure (BP)]. Importantly, HAF dams are exposed to hyperandrogenemia starting pre-pubertally and continuing throughout pregnancy and lactation in order to mimic the conditions in PCOS mothers. Both male and female offspring of HAF dams are born with LBW compared to sex-matched offspring of control dams, as seen in human PCOS offspring. Interestingly, by 16 weeks of age (adults), male offspring of HAF dams are normotensive, but have renal injury and an enhanced pressor response to infused Ang II, signaling an increased risk of hypertension and CVD later in life. In contrast, female offspring of HAF dams are normotensive with no proteinuria, and their BP is refractory to infused Ang II. Taken together, these data suggest that unlike their male counterparts, female offspring of HAF dams are protected against programmed CV risk in adulthood.
The main goal of this project is to identify the mechanisms behind sex differences in adult offspring born to HAF (model of PCOS) using state-of-the-art physiological and molecular techniques. In particular, we will aim at determining the role of sex hormones, intra-renal vasoconstrictor and vasodilator renin angiotensin system, renal regulatory T cells and intra-renal inflammatory cytokines in the observed sex differences.