Hypertension is a leading risk factor for stroke and dementia, but the mechanisms mediating its deleterious effects on the brain remain poorly understood. Hypertension damages the structure and function of cerebral blood vessels increasing the susceptibility of the brain to stroke and cognitive impairment. In particular, hypertension disrupts critical homeostatic mechanisms that assure adequate cerebral perfusion, promoting vascular insufficiency and brain dysfunction. In the hypertension induced by infusion of low doses of angiotensin II (AngII), a peptide involved in human hypertension, or in mice with life-long hypertension on genetic basis (BPH mice), the cerebrovascular dysfunction is mediated by activation of AngII type 1 receptors (AT1R) resulting in vascular oxidative stress produced by a Nox2-containing NADPH oxidase. The cellular target(s) of AngII, its effectors in the vascular wall and the impact of the neurovascular dysfunction on cognition remain to be established and are of great translational relevance. Perivascular macrophages (PVM) are bone marrow derived cells residing in the perivascular space in close apposition to the cerebrovascular basement membrane and express AT1R and Nox2 and, as such, are well positioned to contribute to the cerebrovascular dysfunction induced by AngII-dependent hypertension. The central hypothesis of this application is that PVM are critical cells for the cerebrovascular and cognitive dysfunctio induced by hypertension. To this end, first we will establish whether AngII, infused for 2 weeks, crosses the blood-brain barrier and reaches the PVM in the perivascular space. Second, we will determine whether PVM are required for the cerebrovascular and cognitive alterations induced by AngII infusion. Third, we will determine whether AT1R and Nox2 in PVM are involved in the dysfunction. In parallel studies we will also examine the role of PVM in the cerebrovascular and cognitive dysfunction observed in young and aged mice with life-long hypertension (BPH mice). To achieve these goals we will use state-of-the-art approaches to study neurovascular regulation in combination with bone marrow chimeras and genetic models for cell specific conditional deletion of genes of interest. The findings derived from the proposed studies will fill an obvious gap in our understanding of the cellular mechanisms of the brain dysfunction induced by hypertension, and will provide proof-of-principle that PVM may be a therapeutic target for the devastating effects of hypertension on the brain.
Hypertension remains a major cause of morbidity and mortality in the US and worldwide, stroke and dementia comprising a major portion of its disease burden. This application seeks to pinpoint the cells in the vessel wall that mediate the deleterious effects of angiotensin II, a peptide involved in human hypertension. By identifying the cells mediating these harmful cerebrovascular effects our studies have the potential to unveil new approaches to prevent or treat the damaging effects of hypertension on the brain.
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