Early Life Stress &Chronic Control of Blood Pressure
Principal Investigator: Analia Loria
Abstract: DESCRIPTION (provided by applicant): Chronic adult diseases, such as hypertension, diabetes or obesity, may develop as a consequence of early life stress (ELS). Adverse childhood events are highly correlated with enhanced cardiovascular response to a secondary stressor, a "second hit". Maternal separation is an established model of chronic behavioral stress in rodents that involves separating pups from their mothers 3 hr/day from days 2-14 of life. Adult maternally separated (MS) rats show lower glomerular filtration rate under baseline conditions compared to control, un-separated littermates, with no difference in blood pressure. Interestingly, the phenylephrine-induced vasoconstriction in the kidney is attenuated but the drop in blood pressure elicited by ganglion blockade is greater in MS rats. These data suggest increased sympathetic activation in MS rats. In contrast, the acute pressor response to angiotensin II (AngII) is comparable between MS and control rats whereas MS rats show exaggerated chronic AngII-induced hypertension. Thus, our data suggest that ELS impairs the ability of the kidney to control blood pressure following a "second hit". Taken together, we hypothesize that rats exposed to MS display increased renal sympathetic nerve activity (RSNA), which enhances vascular tone in the kidneys and impairs the physiological regulation of blood pressure. Given the fact that RSNA can increase AngII type 1 (AT1) receptor expression, we speculate that increased baseline RSNA in MS rats results in increased renal AngII system components, predisposing these rats to cardiovascular disease. In an original approach to model the growing epidemic of children with extremely poor dietary lifestyles, we exposed the rats to a high fat diet (HFD) as a secondary stressor. Our data show a fat-induced increase in blood pressure develops in rats exposed to ELS compared to control rats. Furthermore, we observed increased plasma leptin, corticosterone, aldosterone and renin activity in MS rats. These compelling data support the hypothesis that ELS impairs maintenance of blood pressure homeostasis in response to "second hits" in adult life. The mentored phase will focus on the investigation of the RSNA and AT1-dependent mechanisms by which ELS exacerbates AngII-induced hypertension in adult rats, followed by the independent phase focused on the study of mechanisms by which ELS exacerbates blood pressure sensitivity to a HFD in adult rats. This novel proposal will investigate the following four aims: (1) to test the hypothesis that increased RSNA impairs renal capacity to control blood pressure in response to chronic AngII infusion in adult MS rats;(2) to test the hypothesis that exaggerated AT1 receptor activation increases renal vasoconstriction and reduces basal renal filtration capacity, enhancing AngII-induced hypertension in adult MS rats;(3) To test the hypothesis that MS increases sensitivity of blood pressure in response to a HFD through a renal mechanism;and (4) To test the hypothesis that HFD increases AngII in adipose tissue and induces AT1 dependent increase in blood pressure in MS rats.
Funding Period: 2012-05-15 - 2013-09-22
more information: NIH RePORT
- Early life stress induces renal dysfunction in adult male rats but not female ratsAnalia S Loria
Section of Experimental Medicine, Georgia Health Sciences Univ, Augusta, GA 30912, USA
Am J Physiol Regul Integr Comp Physiol 304:R121-9. 2013..These data indicate that during ANG II-induced hypertension, MatSep sensitizes the renal phenotype in male but not female rats...
- Early life stress sensitizes the renal and systemic sympathetic system in ratsAnalia S Loria
Section of Experimental Medicine, CB 2200, 1459 Laney Walker Blvd, Dept of Medicine, Georgia Regents University, Augusta, GA 30912, USA
Am J Physiol Renal Physiol 305:F390-5. 2013..In conclusion, these data indicate that MS sensitizes the renal and systemic sympathetic system ultimately impairing blood pressure regulation...
- Interactive Signaling Modules in Vascular InflammationLinda H Shapiro; Fiscal Year: 2013..abstract_text> ..
- Regulatory Mechanisms In Intestinal MotilityKenton M Sanders; Fiscal Year: 2013..The investigative team is highly synergistic and collaborative, and the PPG has a long track-record of productivity and novel discovery ..
- Novel Mechanisms and Therapies in Heart FailureHoward A Rockman; Fiscal Year: 2013..The results will be used to define novel strategies for manipulation of these recently discovered mechanisms for the therapy of patients with heart failure. ..
- ENDOTHELIN CONTROL OF RENAL HEMODYNAMIC AND EXCRETORY FUNCTIONDavid M Pollock; Fiscal Year: 2013..In particular, this Program will investigate a full range of mechanisms that control ET-1 release and receptor specific actions in order to provide clinically relevant information. ..
- Mechanisms of Microvascular Control and Coordination in Health and DiseaseGerald A Meininger; Fiscal Year: 2013..End of Abstract) ..
- Novel EP receptor antagonists for the treatment of hypertension and of diabetesRichard M Breyer; Fiscal Year: 2013....
- Humoral factors in gender differences in blood pressure controlJane F Reckelhoff; Fiscal Year: 2013..Results from these studies will provide new information that can be used to design new therapeutic options to treat HT in women with hyperandrogenemia, such as in PCOS. ..
- Mechanisms of Health Effects of Exercise in ChildrenDan M Cooper; Fiscal Year: 2013..Collectively, the PPG will promote novel preventive and adjunctive exercise therapies in children with chronic inflammation- therapies grounded in a firm understanding of biological mechanisms. ..
- Signaling Processes Underlying Cardiovascular FunctionJeffrey Robbins; Fiscal Year: 2013..These projects are supported by 3 Cores: Core A: The Administrative Core;Core B: The Physiology Core and Core C: The Imaging-Cell Culture Core. (End of Abstract) ..
- OXIDATIVE STRESS IN THE KIDNEY IN HYPERTENSIONChristopher S Wilcox; Fiscal Year: 2013..These are supported by the Administrative, Animal and Bioanalytical Cores. ..
- Restoring Mycocardial HealingMARK ALAN SUSSMAN; Fiscal Year: 2013..The goal of this program will be to delineate these deleterious signaling mechanisms and determine how they can be overcome to restore endogenous cellular repair processes that heal the damaged heart. ..
- Ether Lipids, Elcosanoids, and Lung Cell PathophysiologyCHRISTINA CARROLL LESLIE; Fiscal Year: 2013..By using multidisciplinary approaches, we will determine the structural identity of lipid mediators, the molecular mechanisms involved in their production and how they function to regulate lung responses. ..
- Multiphoton imaging of the juxtaglomerular apparatusJanos Peti-Peterdi; Fiscal Year: 2013..In this proposal we will directly visualize novel mechanisms in the kidney using a state-of- the-art imaging technology which will allow us to discover how the kidney operates in real time to control blood volume and pressure. ..
- Renal AT2 Receptors in HypertensionROBERT MUNSON CAREY; Fiscal Year: 2013..This application will increase our understanding of the mechanisms whereby the kidney renin-angiotensin system regulates salt and water excretion, suggesting new molecular targets for the treatment and prevention of hypertension. ..
- Interactions of the RAAS and a Western Diet on Insulin Metabolic ActionsJAMES RUSSELL SOWERS; Fiscal Year: 2013..tyrosine (p) and the resultant downstream IRS-1/PI3-K/Akt signaling. ..
- HORMONAL REGULATION OF BLOOD PRESSUREMichal Laniado Schwartzman; Fiscal Year: 2013..ular tone, in the pathophysiology of hypertension and cardiovascular disease. ..
- MOLECULAR GENETICS OF COAGULATION DISORDERSDavid Ginsburg; Fiscal Year: 2013..This Project will identify key genes in this system that should provide valuable new diagnostic tools as well as suggest novel approaches to treatment. ..
- Neurohumoral control of veins in hypertensionGregory D Fink; Fiscal Year: 2013..This project tests the idea that altered structure or function of veins also may cause hypertension, and that it may be possible to treat hypertension using drugs that affect veins. ..
- CARDIOVASCULAR DYNAMICS AND THEIR CONTROLJohn E Hall; Fiscal Year: 2013..End of Abstract) ..