The long term goal of the proposed research project is to(determine the mechanism of acute glucocorticoid-mediated hypertension, a common clinical occurrence that is poorly understood. Traditionally, the mechanism has been thought to be the result of promiscuous activation of the renal mineralocorticoid receptor (MR) by cortisol. However, evidence suggests that the glucocorticoid receptor (GR) in renal and extra-renal tissues may also play a role, especially in the acute phase of this form of hypertension. Preliminary data indicate that this acute phase is likely mediated through changes in vascular tone. This project aims to delineate the role of vascular smooth muscle GR in the acute phase of hypertension. The investigator plans to take advantage of advances in mouse genetics by using an established in vivo mouse model which allows tissue-specific GR knock-out. By using these knock-out mice and two state-of-the-art technologies, including an implantable blood pressure monitoring system and a ultrasound probe which allows measurement^ cardiac output and systemic vascular resistance in vivo, she will be able to evaluate blood pressure responses to a variety of stimuli in an intact organism. The investigator also intends to study the vascular reactivity of isolated vessels from these knock-out mice. The vascular smooth muscle GR knock-out model is a novel reagent that will permit a full characterization of the role of this tissue in acute glucocorticoid-mediated hypertension, which previously has not been possible.
Hypertension is a common clinical disorder and a major public health concern that is poorly understood. This work will provide improved understanding of one particular form of hypertension, lead to insight into more general forms, and direct evolving treatment strategies for hypertension.
|Goodwin, Julie E; Feng, Yan; Velazquez, Heino et al. (2014) Loss of the endothelial glucocorticoid receptor prevents the therapeutic protection afforded by dexamethasone after LPS. PLoS One 9:e108126|
|Goodwin, Julie E; Feng, Yan; Velazquez, Heino et al. (2013) Endothelial glucocorticoid receptor is required for protection against sepsis. Proc Natl Acad Sci U S A 110:306-11|
|Goodwin, Julie E; Zhang, Junhui; Gonzalez, David et al. (2011) Knockout of the vascular endothelial glucocorticoid receptor abrogates dexamethasone-induced hypertension. J Hypertens 29:1347-56|
|Goodwin, Julie E; Zhang, Junhui; Velazquez, Heino et al. (2010) The glucocorticoid receptor in the distal nephron is not necessary for the development or maintenance of dexamethasone-induced hypertension. Biochem Biophys Res Commun 394:266-71|