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.

Public Health Relevance

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.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Method to Extend Research in Time (MERIT) Award (R37)
Project #
Application #
Study Section
Acute Neural Injury and Epilepsy Study Section (ANIE)
Program Officer
Koenig, James I
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Weill Medical College of Cornell University
Schools of Medicine
New York
United States
Zip Code
Merkler, Alexander E; Gialdini, Gino; Lerario, Michael P et al. (2018) Population-Based Assessment of the Long-Term Risk of Seizures in Survivors of Stroke. Stroke 49:1319-1324
Faraco, Giuseppe; Brea, David; Garcia-Bonilla, Lidia et al. (2018) Dietary salt promotes neurovascular and cognitive dysfunction through a gut-initiated TH17 response. Nat Neurosci 21:240-249
Iadecola, Costantino; Gottesman, Rebecca F (2018) Cerebrovascular Alterations in Alzheimer Disease. Circ Res 123:406-408
Mallat, Ziad; Ait-Oufella, Hafid; Tedgui, Alain (2017) The Pathogenic Transforming Growth Factor-? Overdrive Hypothesis in Aortic Aneurysms and Dissections: A Mirage? Circ Res 120:1718-1720
Gorelick, Philip B; Furie, Karen L; Iadecola, Costantino et al. (2017) Defining Optimal Brain Health in Adults: A Presidential Advisory From the American Heart Association/American Stroke Association. Stroke 48:e284-e303
Merkler, Alexander E; Gialdini, Gino; Yaghi, Shadi et al. (2017) Safety Outcomes After Percutaneous Transcatheter Closure of Patent Foramen Ovale. Stroke 48:3073-3077
Merkler, Alexander E; Iadecola, Costantino (2017) Rollercoaster Blood Pressure: An Alzheimer Disease Risk Factor? Circulation 136:526-528
Iadecola, Costantino (2017) The Neurovascular Unit Coming of Age: A Journey through Neurovascular Coupling in Health and Disease. Neuron 96:17-42
Faraco, Giuseppe; Park, Laibaik; Anrather, Josef et al. (2017) Brain perivascular macrophages: characterization and functional roles in health and disease. J Mol Med (Berl) 95:1143-1152
Gusdon, Aaron M; Gialdini, Gino; Kone, Gbambele et al. (2017) Neutrophil-Lymphocyte Ratio and Perihematomal Edema Growth in Intracerebral Hemorrhage. Stroke 48:2589-2592

Showing the most recent 10 out of 28 publications