Resveratrol treatment rescues neurovascular coupling in aged mice: role of improved cerebromicrovascular endothelial function and downregulation of NADPH oxidase

Abstract

Moment-to-moment adjustment of cerebral blood flow (CBF) to neuronal activity via neurovascular coupling is essential for the maintenance of normal neuronal function. Increased oxidative stress that occurs with aging was shown to impair neurovascular coupling, which likely contributes to a significant age-related decline in higher cortical function, increasing the risk for vascular cognitive impairment. Resveratrol is a polyphenolic compound that exerts significant antiaging protective effects in large vessels, but its effects on the cerebromicrovasculature remain poorly defined. The present study was undertaken to investigate the capacity of resveratrol to improve neurovascular coupling in aging. In aged (24-mo-old) C57BL/6 mice N(ω)-nitro-l-arginine methyl ester-sensitive, nitric oxide-mediated CBF responses to whisker stimulation and to the endothelium-dependent dilator acethylcholine (ACh) were impaired compared with those in young (3-mo-old) mice. Treatment of aged mice with resveratrol rescued neurovascular coupling and ACh-induced responses, which was associated with downregulation of cortical expression of NADPH oxidase and decreased levels of biomarkers of oxidative/nitrative stress (3-nitrotyrosine, 8-isoprostanes). Resveratrol also attenuated age-related increases in reactive oxygen species (ROS) production in cultured cerebromicrovascular endothelial cells (DCF fluorescence, flow cytometry). In conclusion, treatment with resveratrol rescues cortical neurovascular coupling responses to increased neuronal activity in aged mice, likely by restoring cerebromicrovascular endothelial function via downregulation of NADPH oxidase-derived ROS production. Beneficial cerebromicrovascular effects of resveratrol may contribute to its protective effects on cognitive function in aging.

IGF‐1 deficiency impairs neurovascular coupling in mice: implications for cerebromicrovascular aging

“…1B), indicating that IGF‐1 deficiency leads to neurovascular uncoupling, mimicking the aging phenotype (Toth et al ., 2014a). IGF‐1 deficiency could reduce functional hyperemia by impairing neural activity evoked by whisker stimulation.…”

“…ACh‐induced CBF responses were significantly attenuated in IGF‐1‐deficient mice (Fig. 2B), supporting the concept that IGF‐1 deficiency impairs cerebromicrovascular endothelial function, mimicking the aging phenotype (Toth et al ., 2014a). Previously, it has been found that in models of vascular aging in the periphery, IGF‐1 decreases vascular oxidative stress and improves endothelial function (Ungvari & Csiszar, 2012), whereas it does not significantly affect endothelium‐independent vasodilation elicited by NO donors (Bailey‐Downs et al ., 2012).…”

“…We found that in IGF‐1‐deficient mice, 3‐nitrotyrosine content in the cerebral cortex is significantly elevated (Fig. 2C) consistent with increased oxidative/nitrosative stress in the brain, which mimics the aging phenotype (Toth et al ., 2014a). IGF‐1 deficiency was associated with decreased expression of Nos3 (Fig.…”

“…Here, we show for the first time that circulating IGF‐1 deficiency also leads to profound neurovascular dysregulation, characterized by impaired CBF responses induced by synaptic activity (Fig. 1), which mimics the cerebromicrovascular aging phenotype (Toth et al ., 2014a). Impairment of a key homeostatic mechanism matching energy supply with the needs of active neuronal tissue is predicted to have deleterious effects on brain function.…”

“…The resulting functional hyperemia is responsible for maintenance of an optimal local microenvironment in the cerebral tissue by increasing delivery of oxygen and glucose and removal of potentially deleterious by‐products of cerebral metabolism. Aging is associated with significant impairment of functional hyperemia (termed ‘neurovascular uncoupling’), and the ensuing disruption of the cerebral microenvironment likely contributes to impairment of higher cerebral function in elderly patients and aged laboratory animals (Zaletel et al ., 2005; Park et al ., 2007; Topcuoglu et al ., 2009; Fabiani et al ., 2013; Sorond et al ., 2013; Stefanova et al ., 2013; Toth et al ., 2014a). Yet, the specific age‐related mechanisms responsible for neurovascular uncoupling are not yet understood.…”