Supplement: Adventitial-Medial Interactions in Thoracic Aortic Diseases

Alzheimer’s disease (AD) is closely linked to cardiovascular risk factors. This includes a well known association between hypertension and AD. The renin-angiotensin system contributes to hypertension through its bioactive peptide angiotensin II (AngII) acting on AT1 receptor. Consequently, there has been considerable interest in exploring whether and how AngII and AT1 receptor contribute to AD and AD-related dementia. In agreement with this potential role of AngII and AT1 receptor interaction in AD, there are now several ongoing clinical trials to determine effects of AT1 receptor antagonism on the progression of AD. The parent grant is studying the role of AngII infusion on the development of aortopathies, with specific focus on the mechanism of ascending aortic aneurysms in mice. We have reported previously that chronic subcutaneous infusion of AngII also causes vascular pathology in the abdominal aorta and the superior mesenteric artery. This mouse model has been extensively used by more than 50 laboratories internationally to study mechanisms of aortic pathologies. However, no studies have explored effects of AngII infusion on cerebral vasculature and cognitive function in this mouse model. In this proposed supplement we will determine whether chronic AngII infusion promotes pathological changes in cerebral vasculature that are correlated with cognitive dysfunction and neural pathology. This project will use the existing mouse model described in the parent grant. Mice will be infused with different dose of AngII (100 - 1000 ng/kg/min) for different durations (4 - 12 weeks) to determine whether AngII induces cerebral vasculature pathologies and cognitive impairment. To determine whether this is a direct effect of AngII or effects of hypertension per se, we will compare AngII and norepinephrine that increase blood pressure to equivalent magnitude on cerebral vasculopathy and cognitive impairment. Since female has higher prevalence of cognitive dysfunction, we will study both male and female mice. The proposed project will be benefitted from the availability of sophisticated microscopy on the University of Kentucky campus that permits detailed characterization of cerebral vascular structure in mice, while cognitive function can be determined using the gold standard for AD of a Morris water maze. Cerebral vascular pathologies and impairment of cognitive function in this mouse model will be further explored by collaboration with neurological scientists in our department.