Although the consequences of microvascular or small vessel disease (SVD) are devastating for brain, there is no specific therapy at present. Knowledge of mechanisms that underlie and might potentially be used to prevent the major consequences of SVD - strokes and cognitive deficits - is very limited. Growing interest in this area, supported by preliminary data, led us to focus on brain parenchymal arterioles, major resistance vessels and preferential targets of the SVD process. These knowledge gaps increase even further when hypertension, the leading risk factor for SVD, is considered. For reasons that are not clear, hypertension is a greater risk factor for stroke than for myocardial infarction. Both systemic and local components of the renin-angiotensin-aldosterone system (RAAS) (including the brain RAAS) contribute to hypertension. We hypothesized that the brain RAAS also affects the local vasculature. In that sense, cerebral vessels may be subjected to both increased intravascular pressure as well as local effects of the brain RAAS during hypertension and potentially other diseases. Our overall hypothesis is that the cerebral circulation is affected by the central RAAS and that the transcription factor peroxisome proliferator-activated receptor-? (PPAR?) in endothelial cells 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. The first is a variation of the deoxycorticosterone acetate (DOCA)-salt model, characterized by activation of the brain RAAS, but suppression of the peripheral RAAS. In the second model, the brain RAAS is activated by genetic manipulation. Preliminary data suggest the central RAAS impacts select endothelial signaling pathways, vasomotor regulation, and produces changes in vascular structure. Interestingly, these effects appear to be specific for cerebral blood vessels.
Aim 2 will use complementary approaches to determine if endothelial PPAR? protects against central RAAS-induced vascular changes via mechanisms that include suppression of angiotensin II receptor expression and function, oxidative stress, and the ROCK2 isoform of Rho kinase. Pilot data support this Aim as well. The proposed Aims build upon our own recent studies as well as these preliminary findings, addressing several major gaps in knowledge. We focus on hypertension, the leading risk factor for strokes, in combination with a unique and critically important segment of the vasculature where surprisingly little is known. Innovative models and approaches will be used that 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. The studies have unquestionable relevance to global health, including the population served by the Department of Veterans Affairs. Our sharing of expertise and resources supports a focus on mechanisms of vascular disease with models and approaches that are unique.
Small vessel disease (SVD) in brain is a key cause of stroke and a major contributor to the vascular component of dementias and other neurological diseases. Hypertension is the greatest risk factor for stroke and a leading cause of SVD. The burden of hypertension in combination with SVD for society, including the population served by the VA, is enormous. Although consequences of SVD are devastating, there is no specific therapy at present. Knowledge of mechanisms that underlie and might potentially be used to prevent SVD is very limited. Our overall hypothesis is that the cerebral circulation is affected by the local brain renin-angiotensin system during hypertension and that specific endothelial-based mechanisms protect against these effects. We focus on a unique and critically important segment of the vasculature where surprisingly little is known using innovative models and approaches.
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