Because it is a major risk factor for cerebrovascular disease and stroke and a leading cause of cognitive decline, hypertension has an enormous negative impact on the brain. End-organ damage to endothelium underlies many forms of cerebrovascular disease with diverse consequences. The renin-angiotensin sys- tem (RAS) and angiotensin II (Ang II) play a fundamental role during hypertension and in the pathogenesis of vascular disease. Detrimental effects of the RAS are commonly due to Ang II acting on AT1 receptors resulting in activation of many downstream targets and oxidative stress. A major barrier to progress for preventing cerebrovascular disease has been our limited understanding of endogenous molecules and pathways that may effectively suppress these processes. Our pilot data suggest the transcription factor peroxisome proliferator-activated receptor- (PPAR) has a major influence on the cerebral circulation with links to the RAS. Using novel mouse models to define cell-specific mechanisms, our overall goal is to determine if endothelial PPAR protects the vasculature in Ang II-dependent models of disease and to define targets or pathways that mediate these effects. To define the role of PPAR in this cell type, we will examine the hypothesis that interference with endothelial PPAR augments Ang-II induced vascular dysfunction and abnormal vascular growth (Aim 1). As part of this Aim we will also determine if increased expression of wild-type PPAR in endothelium protects against detrimental structural and functional effects. Our preliminary data suggest genetic interference with endothelial PPAR increases expression of NADPH oxidase and augments Ang II-induced vascular dysfunction while increased endothelial expression of wild- type PPAR inhibits vascular effects of Ang II. In contrast to Ang II, the RAS can exert beneficial effects via the actions of Ang (1-7).
Aim 2 will unravel a previously unknown interaction and determine if Ang (1-7) and its receptor are targets of endothelial PPAR. We will determine if interference with endothelial PPAR impairs vascular effects of the Ang (1-7) arm of the RAS and define mechanisms involved. Our preliminary data support this hypothesis. We suggest PPAR and select targets in endothelium are part of a previously unrecognized mechanism that suppresses detrimental effects of Ang II. The balance between PPAR and the RAS (and their respective targets) in endothelium may be a major determinant of the onset and pro- gression of carotid and cerebrovascular disease. Defining key connections between PPAR and the RAS may ultimately lead to more specific therapeutic targeting for vascular disease that leads to stroke and/or contributes to the vascular component of Alzheimers disease and hypertension-induced cognitive impairment.
Hypertension is a major health problem affecting approximately one-third of the adult US population, including veterans. Hypertension is a major risk factor for cerebrovascular disease and stroke and is a leading cause of dementia. The renin-angiotensin system plays a key role in hypertension but also promotes atherosclerosis and vascular disease due to other risk factors, including diabetes and aging. The overall goal of this project is to identify endothelial-specific mechanisms that protect the vasculature during hypertension and in models of angiotensin-dependent vascular disease. Such insight may ultimately lead to improved therapeutic approaches for vascular disease that is the major cause of stroke, but also contributes to the vascular component of Alzheimer's disease and dementia.
|Hu, Xiaoming; De Silva, T Michael; Chen, Jun et al. (2017) Cerebral Vascular Disease and Neurovascular Injury in Ischemic Stroke. Circ Res 120:449-471|
|Baron-Menguy, Celine; Domenga-Denier, Valérie; Ghezali, Lamia et al. (2017) Increased Notch3 Activity Mediates Pathological Changes in Structure of Cerebral Arteries. Hypertension 69:60-70|
|Faraci, Frank M (2017) Disease Highlights the Cellular Diversity of Neurovascular Units: Sign in Stranger. Circ Res 121:203-205|
|Ketsawatsomkron, Pimonrat; Keen, Henry L; Davis, Deborah R et al. (2016) Protective Role for Tissue Inhibitor of Metalloproteinase-4, a Novel Peroxisome Proliferator-Activated Receptor-? Target Gene, in Smooth Muscle in Deoxycorticosterone Acetate-Salt Hypertension. Hypertension 67:214-22|
|De Silva, T Michael; Faraci, Frank M (2016) Microvascular Dysfunction and Cognitive Impairment. Cell Mol Neurobiol 36:241-58|
|De Silva, T Michael; Kinzenbaw, Dale A; Modrick, Mary L et al. (2016) Heterogeneous Impact of ROCK2 on Carotid and Cerebrovascular Function. Hypertension 68:809-17|
|De Silva, T Michael; Ketsawatsomkron, Pimonrat; Pelham, Christopher et al. (2015) Genetic interference with peroxisome proliferator-activated receptor ? in smooth muscle enhances myogenic tone in the cerebrovasculature via A Rho kinase-dependent mechanism. Hypertension 65:345-51|
|Peña Silva, Ricardo A; Mitchell, Ian J; Kung, David K et al. (2015) Paradoxical Increase in Mortality and Rupture of Intracranial Aneurysms in Microsomal Prostaglandin E2 Synthase Type 1-Deficient Mice: Attenuation by Aspirin. Neurosurgery 77:613-20|
|Hasan, David M; Starke, Robert M; Gu, He et al. (2015) Smooth Muscle Peroxisome Proliferator-Activated Receptor ? Plays a Critical Role in Formation and Rupture of Cerebral Aneurysms in Mice In Vivo. Hypertension 66:211-20|
|Chrissobolis, Sophocles; Drummond, Grant R; Faraci, Frank M et al. (2014) Chronic aldosterone administration causes Nox2-mediated increases in reactive oxygen species production and endothelial dysfunction in the cerebral circulation. J Hypertens 32:1815-21|