Although the consequences of small vessel disease (SVD) are devastating for brain, there are no specific therapies at present. Knowledge of mechanisms that underlie and might potentially be used to prevent SVD and its effects, which include strokes and cognitive deficits, is very limited. Brain parenchymal arterioles are important resistance vessels and preferential targets of SVD. Hypertension is a the leading risk factor for SVD. For reasons that are not clear, hypertension is a greater risk factor for stroke than for myocardial infarction. Although the brain renin-angiotensin-aldosterone system (RAAS) contributes to hypertension, it is not known if it also affects the local vasculature. In that sense, cerebral vessels may be subjected to both increased intravascular pressure as well as local effects during activation of the brain RAAS. Our overall hypothesis is that the cerebral circulation is affected by the central RAAS and that endothelial peroxisome proliferator-activated receptor-γ (PPARγ) protects against such effects. We propose two Specific Aims. Aim 1 uses two models to determine if activation of the brain RAAS affects function, structure, or mechanics of cerebral arteries and parenchymal arterioles. One is a recent variation of the DOCA-salt model, characterized by activation of the brain RAAS, but suppression of the peripheral RAAS. In the second, the brain RAAS is activated by genetic manipulation. Preliminary data suggest the central RAAS impacts select signaling pathways, vasomotor regulation, and vascular structure. Interestingly, these effects were specific for cerebral vessels. Aim 2 will determine if endothelial PPARγ protects against central RAAS-induced vascular changes via mechanisms that include suppression of angiotensin II receptors, oxidative stress, and the ROCK2 isoform of Rho kinase. Pilot data support this Aim as well. The premise for these studies fit well within the goals of this RFA, focusing on novel mechanisms that underlie SVD during hypertension. The models exhibit features making them representative of a greater percentage of people with essential hypertension compared to more common approaches. Pilot data reveal vascular heterogeneity that contributes to increased susceptability of the brain circulation during hypertension. In summary, the impact of SVD is great, but our understanding of the underlying vascular biology and the impact of hypertension on the brain vasculature in lacking. Using innovative models and approaches, the proposed work will fill gaps identified in the literature and by the scientific community regarding needed advances in our understanding of SVD, vascular biology, and impact of hypertension on the brain vasculature. This area of study has unquestionable relevance to global health. Our sharing of expertise and resources supports a focus on mechanisms of SVD with models and approaches and concepts that are unique.