1: Loria Lab interests: Early life Stress and cardiovascular disease risk

The development of CVD is strongly influenced by lifestyle and environment that determine the impact of traditionally defined risk factors, such as obesity and hypertension. Among those lifestyle factors, a large number of clinical and epidemiological studies have identified early life stress (ELS) as an independent risk factor for metabolic syndrome, type 2 diabetes mellitus and ischemic heart disease in adult life. ELS is defined by exposure to physical or emotional distress, sexual abuse and neglect experienced during the first decade of life. The Adverse Childhood Experiences Study performed in 17,000 middle-aged Caucasians linked childhood trauma to the incidence of chronic disease including heart disease and diabetes.18 Findings from the Georgia Stress and Heart (GSH) study, a 23-year follow up study including 213 African Americans and 181 European Americans, revealed that individuals exposed to multiple ELS factors display a greater increase in BP levels compared to control individuals. Recently, retrospective findings from the 1958 British Birth Cohort Study (n= 6,714 members), revealed that metabolic risk was higher among people with psychological distress in childhood only, and persistent across the life course. This robust unbiased study included a large unselected sample, 45-year follow-up span, prospective measures of psychological distress and multiple data collection sources/methods. However, to date, experimental paradigms to test the mechanistic interplay between ELS and CVD risk are missing, demanding the validation of models to decipher the underlying mechanisms. Our preliminary studies identify the adipose tissue-brain axis as a potential innovative target for the prevention and treatment of CVD in individuals at higher risk.

This scientific premise is based on the following strengths:
1. We use a mouse model of neglect to identify causative factors that link ELS and CVD risk: The maternal separation model has been applied in various designs in rats and mice to test the long-term effects of chronic stress during postnatal life on behavior, implicating overactivation of the hypothalamic pituitary adrenal (HPA) axis, SNS and RAS. Importantly, this model has been shown to mimic the effect of ELS on the cardiovascular system as well. While some studies suggest that this effect wanes over long-term, many studies have shown that exposure to a secondary stressor (or second hit) is required to provoke exacerbated responses. There is a lack of studies addressing the relative contributions of HPA, SNS and RAS to obesity-induced hypertension. We utilize a unique mouse model of neglect that combines maternal separation and early weaning, termed MSEW, followed by high fat diet starting at weaning. Consistent with other reports, we found that MSEW does not reduce body weight or induce a catch-up growth effect in the weanlings, a hallmark of developmental programming of hypertension in non-behavioral fetal programing models. Notably, MSEW exacerbates adiposity and blood pressure in mice fed a HFD. Thus, we propose a tremendously advantageous tool to investigate the mechanisms involved in the ELS-induced trajectory of disease from postnatal to adult life. This study will advance the cardiovascular field, Developmental Origins of Health and Disease (DOHaD), by deciphering the role of ELS-programmed fat-to brain signals on CVD risk.

2. We investigate the the role of adipose afferent reflex (AAR)-mediated SNS activation in mice exposed to MSEW. Despite compelling evidence of disturbances in the central nervous system and autonomic networks associated with obesity-induced HT in humans and animal models, effects on afferent pathways have been underappreciated. Sensory neurons in adipose tissue are receptive to a variety of somatosensory signals that increase the SNS drive to adipose tissue, liver, adrenal medulla, and kidney in a positive feedback involving an adipose sensory-brain-SNS circuit or AAR. Despite AAR’s function is assessed by increases in nerve activity, plasma catecholamines and BP in response to adipose tissue afferent nerve nociceptive stimulation using low doses of capsaicin. However, it has also been shown that leptin receptor type b (Or-Rb) is expressed in sensory neurons as well, mediating these effects. The paraventricular nucleus (PVN) of the hypothalamus, which is an important integrative site influencing the sympathetic tone and thus BP, has been shown to play a pivotal role in the AAR pathway. Our preliminary data indicates that MSEW mice may be susceptible to AAR hyper-excitability.

3. Our study focus on the adipose tissue-derived angiotensinogen (AGT) contribution to obesity-induced HT in MSEW mice. A robust correlation between increased AGT levels and HT has been shown particularly in obese patients. While the liver is the major source of AGT, adipose tissue has emerged as a contributor to obesity-induced HT. We are investigating the contribution of tissue-specific RAS on blood pressure increases in MSEW mice with the inducible abrogation of the AGT gene.

Images: