DESCRIPTION (provided by applicant): Salt consumption worldwide greatly exceeds minimal requirements, and excessive dietary salt has emerged as a powerful risk factor for cardiovascular diseases, especially stroke. A high salt diet (HSD) is particularly damaging in older people. Although the deleterious effect of HSD was first attributed to the hypertension that develops in salt-sensitive individuals, increasing evidence indicates that dietary salt increases the incidence of stroke independently of whether or not the blood pressure is elevated. However, it remains to be established how HSD acts on the brain to increase cerebrovascular risk independently of hypertension. International attempts to curb salt consumption have met with limited success and there is an ongoing controversy about ideal levels of salt intake. Therefore, there have been calls for gaining a better mechanistic understanding of how dietary salt impacts the vascular health of the brain. Recent evidence indicates that HSD induces the expansion of a select population of T-helper lymphocytes in the gut (Th17 cells), which produce IL17, a cytokine well known for its damaging vascular effects in animals and humans. Indeed, diseases driven by a Th17 immune response, such as rheumatoid arthritis, psoriasis, multiple sclerosis or inflammatory bowel disease, are associated with increased risk of stroke. On these bases, we propose to test the central hypothesis that HSD exerts its deleterious cerebrovascular effects by inducing a Th17 response. The resulting increase in the vasotoxic cytokine IL17, in turn, acts on cerebral blood vessels to alter critical homeostatic responses that control cerebral perfusion and safeguard brain health. To this end, the present grant application will examine neurovascular function in a mouse model of HSD (4 or 8% NaCl for 8 weeks) to test the following hypotheses in young and aging mice: (1) HSD alters microvascular structure and function to disrupt key cerebrovascular regulatory mechanisms that assure that the brain receives sufficient blood flow well matched to its energetic needs; (2) The cerebrovascular dysfunction is mediated by Th17 lymphocytes via the cytokine IL17; (3) IL17, in turn, causes cerebrovascular dysfunction by inducing NADPH oxidase-dependent oxidative stress, as well as by modulating the phosphorylation state of endothelial nitric oxide synthase and suppressing nitric oxide production. The proposed studies fill an obvious gap in the understanding of the cerebrovascular effects of HSD across the lifespan, and open new avenues of translational research to develop rational strategies to contain the impact of salt on brain vascular health. Furthermore, the concept that Th17 responses initiated in other organs may alter cerebrovascular structure and function has far reaching consequences for Th17-dependent diseases associated with increased stroke risk.