Effects of Hypertension and Hypoperfusion on the Brain Vasculome Hypertension and hypoperfusion are major risk factors for cerebrovascular disease and vascular cognitive impairment. However, the underlying mechanisms of disease and potential therapeutic targets remain to be fully elucidated. This project will assess the effects of hypertension and cerebral hypoperfusion on the ?vasculome? of the brain, and test the overall hypothesis that blood pressure medications and running exercise can renormalize the diseased brain vasculome and rescue vascular cognitive impairment. Our pilot data suggest that: (i) microvessel endothelial gene expression profiles (i.e. the ?vasculome?) are organ-specific (e.g. the brain vasculome is unique and different from heart etc); (ii) the brain vasculome is affected by hypertension and hypoperfusion in specific ways; (iii) aerobic treadmill running exercise may partially renormalize the diseased brain vasculome in hypertensive rats and mice; (iv) exercise may also rescue cognitive deficits in hypoperfused mice; and (v) in vivo optical imaging is a feasible method for quantifying microvessels in gray and white matter in mice. Based on these initial data, we will pursue 3 integrated aims.
In Aim 1, we will map the effects of cerebral hypoperfusion on the brain vasculome in hypertensive BPH vs normotensive BPN mice.
In Aim 2, we ask whether two ?standard? blood pressure medications (the angiotensin-converting-enzyme inhibitor enalapril and the calcium channel blocker amlodipine) can renormalize the diseased brain vasculome and rescue cognitive deficits in young vs old hypoperfused- hypertensive BPH mice. Finally, Aim 3 will ask whether treadmill running exercise can also renormalize the brain vasculome and rescue cognitive deficits in young vs old hypoperfused-hypertensive BPH mice, independent of blood pressure pathways. Molecular profiles of the vasculome will be obtained with RNAseq. Structure and hemodynamics of microvessels are mapped with in vivo optical imaging. Therapeutic effects will be assessed with neurologic testing. We anticipate 3 ?deliverables?: (i) test the hypothesis that blood pressure meds and exercise can renormalize the diseased brain vasculome and rescue neurologic deficits; (ii) even if our ?blood pressure and exercise hypothesis? is incorrect, our project should still develop the hypoperfused BPH mouse as a potential animal model for mimicking small vessel CNS disease and vascular cognitive impairment; (iii) even if our ?blood pressure and exercise hypothesis? is incorrect, our project will generate a comprehensive database of the diseased brain vasculome in gray vs white matter in aged males vs females.

Public Health Relevance

Effects of hypertension and hypoperfusion on the brain vasculome Hypertension and cerebral hypoperfusion are major risk factors for cerebrovascular disease and dementia. However, the underlying mechanisms remain unclear. This project will develop a mouse model of vascular cognitive impairment using prolonged cerebral hypoperfusion in hypertensive BPH mice. We will use this mouse model to map the effects of hypertension and hypoperfusion on the brain vasculome. We will test the hypothesis that blood pressure meds and exercise can rescue the diseased brain vasculome and ameliorate cognitive deficits. This project should produce the first comprehensive database of the brain vasculome, its response to disease, and potential therapeutic targets and pathways for vascular cognitive impairment.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS110818-01
Application #
9709899
Study Section
Brain Injury and Neurovascular Pathologies Study Section (BINP)
Program Officer
Koenig, James I
Project Start
2019-03-15
Project End
2024-02-29
Budget Start
2019-03-15
Budget End
2020-02-29
Support Year
1
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02114