DESCRIPTION (provided by applicant): 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-γ (PPARγ) exerts protective effects in the vasculature. Our preliminary data suggest expressing a human dominant negative form of PPARγ 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 PPARγ is sufficient on its own to cause endothelial dysfunction. Our overall hypothesis is that endothelial PPARγ (and PPARγ 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 PPARγ 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 PPARγ accelerates microvascular aging and cognitive deficits via oxidative stress-dependent mechanisms. Complementary experiments will examine if increased expression of wild-type PPARγ 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.