There is evidence that aldosterone is involved in the pathophysiology of human essential hypertension. Aldosterone antagonism with spironolactone reduces ischemic cerebral infarct size without lowering blood pressure in stroke prone spontaneously hypertensive rats (SHRSP). This finding is important because the mechanism by which hypertension increases the risk of cerebral ischemia is unknown. An increased responsiveness of vascular smooth muscle cells to epidermal growth factor (EGF) may be responsible for the smaller lumen diameter and thicker walls seen in the cerebral blood vessels of SHRSP, and this may exacerbate the damage caused by ischemia. Aldosterone has been shown to increase EGF receptor (EGFR) phosphorylation and activation, and EGFR mRNA increased in the cerebral blood vessels of SHRSP, which is decreased by spironolactone. We hypothesize that aldosterone increases cerebral infarct size and cerebral blood vessel wall thickness, and reduces vessel lumen diameter by two independent mechanisms: 1) aldosterone activates the classical mineralocorticoid receptors to increase EGFR expression; and 2) aldosterone binds to the mineralocorticoid receptors in the caveolae to elicit a rapid increase in EGFR phosphorylation. In vivo and in vitro techniques will be used to test the specific aims.
Aim 1 will test the hypothesis that aldosterone increases ischemic cerebral infarct size and cerebral blood vessel wall thickness and reduces lumen diameter independently of changes in blood pressure.
Aim 2 will test the hypothesis that aldosterone increases the expression of the EGFR through the mineralocorticoid receptors, and Aim 3 will test the hypothesis that aldosterone directly enhances EGFR activation in vascular smooth muscle cells via a caveolae dependent mechanism. These studies will elucidate a novel role for aldosterone in the pathogenesis of cerebrovascular disease, they will show that aldosterone not only increases EGFR density but also acts as a signaling molecule to enhance EGFR activation. ? ?
|Pires, Paulo W; Girgla, Saavia S; McClain, Jonathon L et al. (2013) Improvement in middle cerebral artery structure and endothelial function in stroke-prone spontaneously hypertensive rats after macrophage depletion. Microcirculation 20:650-61|
|Pires, Paulo W; Rogers, Curt T; McClain, Jonathon L et al. (2011) Doxycycline, a matrix metalloprotease inhibitor, reduces vascular remodeling and damage after cerebral ischemia in stroke-prone spontaneously hypertensive rats. Am J Physiol Heart Circ Physiol 301:H87-97|
|Rigsby, Christine S; Ergul, Adviye; Portik Dobos, Vera et al. (2011) Effects of spironolactone on cerebral vessel structure in rats with sustained hypertension. Am J Hypertens 24:708-15|
|Schreihofer, Derek A; Deutsch, Christian; Lovekamp-Swan, Tara et al. (2010) Effect of high soy diet on the cerebrovasculature and endothelial nitric oxide synthase in the ovariectomized rat. Vascul Pharmacol 52:236-42|
|Pires, Paulo Wagner; Deutsch, Christian; McClain, Jonathon Lee et al. (2010) Tempol, a superoxide dismutase mimetic, prevents cerebral vessel remodeling in hypertensive rats. Microvasc Res 80:445-52|
|Osmond, Jessica M; Dorrance, Anne M (2009) 11beta-hydroxysteroid dehydrogenase type II inhibition causes cerebrovascular remodeling and increases infarct size after cerebral ischemia. Endocrinology 150:713-9|
|Dorrance, Anne M (2009) Are macrophages the foot soldiers in the war waged by aldosterone against the heart? Hypertension 54:451-3|
|Deutsch, Christian; Portik-Dobos, Vera; Smith, Anita D et al. (2009) Diet-induced obesity causes cerebral vessel remodeling and increases the damage caused by ischemic stroke. Microvasc Res 78:100-6|
|Osmond, Jessica M; Rigsby, Christine'S; Dorrance, Anne M (2008) Is the mineralocorticoid receptor a potential target for stroke prevention? Clin Sci (Lond) 114:37-47|
|Rigsby, Christine S; Burch, Ashley E; Ogbi, Safia et al. (2007) Intact female stroke-prone hypertensive rats lack responsiveness to mineralocorticoid receptor antagonists. Am J Physiol Regul Integr Comp Physiol 293:R1754-63|
Showing the most recent 10 out of 17 publications