Abstract TP127: Hypertension Provokes Development Of Cerebral Microhemorrhages In A Mouse Model

Abstract

Introduction: Cerebral microhemorrhages (CMH) are the pathological substrate for cerebral microbleeds, represent focal hemosiderin deposits on MRI, and are associated with increased risk of cognitive impairment and ischemic and hemorrhagic stroke. Aging and hypertension are the most common risk factors for cerebral microbleeds. In this study, we analyzed the effect of hypertension on the development of CMH in a mouse model of aging. Methods: Hypertension was induced in aged (17 months old) female and male C57BL/6J mice, via infusion of angiotensin II (ATII) at 1000 ng/kg/min via Alzet pump over four weeks. We further examined underlying mechanism by inhibiting ATII type 1 receptor (AT1R) with telmisartan, via drinking water for 4 weeks. We collected mouse brains and performed standard histology using Prussian blue staining to detect CMH formation at 20x magnification. We also examined correlations between CMH burden and systolic (SBP) and diastolic (DPB) blood pressures. Results: ATII infusion induced significant increases in SBP (121±4 mmHg to 159±6 mmHg; p<0.001) and DBP (94±4 mmHg to 129±7 mmHg; p<0.001). Telmisartan completely blocked ATII-induced blood pressure elevation. Hypertension increased the number of CMH (p=0.01) in male and female mice. In animals with ATII infusion, number of CMH were positively correlated with SBP (r=0.45, p=0.02) and DBP (r=0.47, p=0.01). Telmisartan reduced by 55% the number of ATII-induced CMH, but compared to controls, CMH number remained elevated (p=0.03) in telmisartan-treated animals. Conclusions: ATII-induced hypertension promotes the development of CMH in aged mice in a manner that appears dependent on the extent of hypertension. However, in the presence of ATII with ATIR blockade, CMH develops even in the absence of hypertension. These findings emphasize the importance of presence and extent of hypertension in development of CMH in aging, as well as the significance of non-AT1R-mediated pathways independent of hypertension in ATII-induced CMH.