The consequences of microvascular or small vessel disease (SVD) are particularly devastating for brain. Knowledge of mechanisms that underlie, and might potentially be used to treat, SVD are very limited. Growing interest in the pathogenesis of SVD, supported by our preliminary data, led us to focus on brain parenchymal arterioles, major resistance vessels and a preferential target of the SVD process. This knowledge gap increases even further when aging, a major risk factor for vascular disease, is considered. Endothelial dysfunction is a critical determinant of vascular disease and predictor of clinical events. The transcription factor peroxisome proliferator-activated receptor-? (PPAR?) exerts protective effects in the vasculature. Our preliminary data suggest expressing a human dominant negative form of PPAR? in endothelium has no effect in large arteries in adult mice at baseline but when combined with aging, induces severe vascular dysfunction. In brain microvessels, interference with endothelial PPAR? is sufficient on its own to cause endothelial dysfunction. Our overall hypothesis is that endothelial PPAR? (and PPAR? targets) protect against oxidative stress and microvascular dysfunction normally and that loss of this protective network augments vascular dysfunction and cognitive deficits with aging.
Aim 1 uses mice with cell-specific genetic manipulations along with physiological and pharmacological approaches to examine mechanisms by which interference with endothelial PPAR? impairs microvascular function, structure, and mechanics. Pilot experiments suggest oxidative stress and activation of Rho kinase play a key role in these effects. Vascular disease and cognition are associated but the relationship is based mainly on the temporal relationship between these endpoints. Experiments to determine if vascular specific manipulations can promote or protect against cognitive deficits have been lacking. We will explore this concept directly by testing if genetic manipulation of endothelium in mice affects age-induced vascular dysfunction and cognitive deficits.
In Aim 2, we will combine cell specific genetic approaches with aging to determine if interference with endothelial PPAR? accelerates microvascular aging and cognitive deficits via oxidative stress-dependent mechanisms. Complementary experiments will examine if increased expression of wild-type PPAR? in endothelium inhibits microvascular aging and the associated cognitive deficits. Pilot data support this hypothesis. Thus, the overall goal of these studies is o define cell-specific molecular determinants of microvascular endothelial dysfunction. We focus on a unique and critically important segment of the vasculature where surprisingly little is known. The studies will fill gaps identified by the NIH regarding the need for understanding of SVD, vascular geroscience, and their impact on brain vascular function and cognitive deficits.
Disease of small blood vessels in brain causes stroke and may be an important contributor to cognitive deficits that occur in many people with aging or hypertension. These studies focus on this critically important segment of the vasculature, examining the role of select pathways in endothelial cells that may protect against microvascular aging and cognitive decline. Our ultimate goal is to identify novel therapeutic targets that can prevent, delay, and possibly reverse this disease process.
|De Silva, T Michael; Li, Ying; Kinzenbaw, Dale A et al. (2018) Endothelial PPAR? (Peroxisome Proliferator-Activated Receptor-?) Is Essential for Preventing Endothelial Dysfunction With Aging. Hypertension 72:227-234|
|De Silva, T Michael; Modrick, Mary L; Dabertrand, Fabrice et al. (2018) Changes in Cerebral Arteries and Parenchymal Arterioles With Aging: Role of Rho Kinase 2 and Impact of Genetic Background. Hypertension 71:921-927|
|Faraci, Frank M (2018) Watching Small Vessel Disease Grow. Circ Res 122:810-812|
|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|
|De Silva, T Michael; Hu, Chunyan; Kinzenbaw, Dale A et al. (2017) Genetic Interference With Endothelial PPAR-? (Peroxisome Proliferator-Activated Receptor-?) Augments Effects of Angiotensin II While Impairing Responses to Angiotensin 1-7. Hypertension 70:559-565|
|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|
|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|