In this study we investigated the contribution of PVMs to the neurovascular and cognitive dysfunction induced by hypertension. We found that depletion of PVMs in models of chronic hypertension suppresses vascular oxidative stress and ameliorates the attendant impairment in neurovascular coupling and endothelium-dependent responses. Studies in bone marrow (BM) chimeras provided evidence that the dysfunction is mediated by ANGII acting on PVM AT1Rs resulting in NOX2-dependent ROS production. Importantly, concomitant to the neurovascular improvement, PVM depletion also rescued cognitive dysfunction. The findings unveil a previously unrecognized role of PVMs in the neurovascular and cognitive dysfunction induced by hypertension, and identify PVMs as a novel pathogenic component of the NVU of critical importance for brain health.

A diet rich in salt is linked to an increased risk of cerebrovascular diseases and dementia, but it remains unclear how dietary salt harms the brain. We report that, in mice, excess dietary salt suppresses resting cerebral blood flow and endothelial function, leading to cognitive impairment. The effect depends on expansion of TH17 cells in the small intestine, resulting in a marked increase in plasma interleukin-17 (IL-17). Circulating IL-17, in turn, promotes endothelial dysfunction and cognitive impairment by the Rho kinase-dependent inhibitory phosphorylation of endothelial nitric oxide synthase and reduced nitric oxide production in cerebral endothelial cells. The findings reveal a new gut-brain axis linking dietary habits to cognitive impairment through a gut-initiated adaptive immune response compromising brain function via circulating IL-17. Thus, the TH17 cell-IL-17 pathway is a putative target to counter the deleterious brain effects induced by dietary salt and other diseases associated with TH17 polarization.

The cAMP responsive element-binding protein (CREB) functions in a broad array of biological and pathophysiological processes. We found that saltinducible kinase 2 (SIK2) was abundantly expressed in neurons and suppressed CREB-mediated gene expression after oxygen-glucose deprivation (OGD). OGD induced the degradation of SIK2 protein concomitantly with the dephosphorylation of the CREB-specific coactivator transducer of regulated CREB activity 1 (TORC1), resulting in the activation of CREB and its downstream gene targets. Ca 2+ / calmodulin-dependent protein kinase I/IV are capable of phosphorylating SIK2 at Thr484, resulting in SIK2 degradation in cortical neurons. Neuronal survival after OGD was significantly increased in neurons isolated from sik2 À/À mice, and ischemic neuronal injury was significantly reduced in the brains of sik2 À/À mice subjected to transient focal ischemia. These findings suggest that SIK2 plays critical roles in neuronal survival, is modulated by CaMK I/IV, and regulates CREB via TORC1.

Cyclodextrins (CyDs) at higher concentrations were found to cause hemolysis of human erythrocytes in the order of beta- greater than alpha- greater than gamma-CyD in isotonic solution. Biphasic effects of CyDs were observed for the osmotic and heat-induced hemolysis; i.e. the protection at relatively low CyD concentrations and stimulation at higher CyD concentrations. From the scanning electron microscopic observations, CyDs induced shape changes of membrane internalization type on erythrocytes. CyDs caused the release of cholesterol from erythrocyte membrane in the order of beta- greater than gamma- greater than alpha-CyD. These results clearly indicate that CyD-induced hemolysis is probably a secondary event resulting from the membrane disruption which elicited the removal of membrane components from erythrocytes.