Prolonged elevations of glucocorticoids cause cardiovascular disease by generating risk factors including hypertension, abdominal obesity, hyperglycemia, insulin resistance, elevated triglycerides and cardiac arrhythmia. Stress is a common cause of moderately elevated glucocorticoids, and stress is also a risk factor for hypertension, obesity and cardiovascular disease. Despite the strong relationship between glucocorticoids, stress and cardiovascular disease, the precise mechanisms linking increased glucocorticoid activity and cardiovascular disease have not been elucidated. Our long-term goal is to identify the central neural pathways and mechanisms by which glucocorticoids and stress modulate central nervous system control of cardiovascular function in order to discover potential new opportunities for clinical intervention. Based on published data and our preliminary results, we have formulated the hypothesis that the naturally occurring glucocorticoid corticosterone (Cort) acts via both mineralocorticoid (MR) and glucocorticoid (GR) receptors to modulate stress responsiveness and baroreflex function by diminishing inhibitory and/or recruiting excitatory effects of catecholaminergic neurons in the nucleus of the solitary tract (NTS). The NTS is a region in the dorsal hindbrain that is important for blood pressure regulation. Experiments will be performed in male Wistar-Kyoto and Borderline Hypertensive Rats (BHR). We hypothesize that the increased genetic susceptibility to stress-induced hypertension in the BHR is due in part to an increased sensitivity to the adverse effects of Cort.
Aims 1 and 2 utilize a validated technique to chronically deliver steroids selectively to the dorsal hindbrain by implantation of small pellets. The pellets will be composed of the following steroids: Cort, Mifepristone (a GR receptor antagonist), eplerenone (an MR receptor antagonist) and/or cholesterol. The secretion of endogenous Cort will be stimulated by stress.
Aims 2 and 3 utilize AAV2 viral vector-mediated gene delivery by local microinjection into the NTS. The vectors will mediate expression of either green fluorescent protein or 11ss-hydroxysteroid dehydrogenase 2, which is the enzyme that metabolizes Cort into an inactive steroid. The synthetic dopamine-ss-hydroxylase promoter PRSx8 will be used to drive expression of the transgenes selectively in catecholaminergic neurons. The expression of GFP will be used as a control in Aim 2, and to label NTS catecholaminergic neurons in Aim 3. Microinjection of the viral vector constructs into the NTS will ensure that the transgene expression is regionally specific.
Aims 1 and 2 are comprised of physiological experiments that will be performed in conscious rats using radiotelemetry to measure blood pressure.
Aim 3 uses anatomical approaches to test the hypothesis that that GR and MR are expressed in discrete sub-populations of NTS catecholaminergic projection neurons that express unique phenotypic markers that differ between BHR and Wistar-Kyoto rats. The results of these experiments will increase our understanding of the mechanisms that link stress and cardiovascular disease.
It is now understood that people who have a high level of stress in their lives and/or react excessively to stress have an increased risk for cardiovascular disease. Sources of stress that have been shown to increase cardiovascular disease risk are common;they include financial strain, marital strife and difficult work situations. The proposed research would help us to understand how stress and stress hormones cause increased cardiovascular disease risk, and thus will have the potential to provide society with cost-effective approaches for the prevention and treatment of cardiovascular disease that are based on stress-reduction interventions.
|Erdos, Benedek; Backes, Iara; McCowan, Michael L et al. (2015) Brain-derived neurotrophic factor modulates angiotensin signaling in the hypothalamus to increase blood pressure in rats. Am J Physiol Heart Circ Physiol 308:H612-22|
|Daubert, Daisy L; McCowan, Michael; Erdos, Benedek et al. (2012) Nucleus of the solitary tract catecholaminergic neurons modulate the cardiovascular response to psychological stress in rats. J Physiol 590:4881-95|
|Scheuer, Deborah A (2010) Regulation of the stress response in rats by central actions of glucocorticoids. Exp Physiol 95:26-31|
|Bechtold, Andrea G; Patel, Gina; Hochhaus, Guenther et al. (2009) Chronic blockade of hindbrain glucocorticoid receptors reduces blood pressure responses to novel stress and attenuates adaptation to repeated stress. Am J Physiol Regul Integr Comp Physiol 296:R1445-54|
|Bechtold, Andrea G; Vernon, Kathy; Hines, Tina et al. (2008) Genetic predisposition to hypertension sensitizes borderline hypertensive rats to the hypertensive effects of prenatal glucocorticoid exposure. J Physiol 586:673-84|
|Scheuer, Deborah A; Bechtold, Andrea G; Vernon, Kathy A (2007) Chronic activation of dorsal hindbrain corticosteroid receptors augments the arterial pressure response to acute stress. Hypertension 49:127-33|
|Bechtold, Andrea G; Scheuer, Deborah A (2006) Glucocorticoids act in the dorsal hindbrain to modulate baroreflex control of heart rate. Am J Physiol Regul Integr Comp Physiol 290:R1003-11|