Effects of exercise training on microvascular changes in aging rat brain : roles of VEGF and eNOS

Abstract

Aging has been reported to increase risk of cerebrovascular diseases. Reduction of basal regional blood flow and capillary loss in the brain contribute tissue perfusion insufficiency with advancing age. Microvascular deterioration in aged brain appears to be related to downregulation of vascular endothelial growth factor (VEGF) and endothelial nitric oxide synthase (eNOS), which both are key modulators related age-induced microvascular changes. Regular physical exercise is well known to have beneficial effect to brain health, including promoted blood flow, augmented angiogenesis and enhanced vascularization, in aging individuals. However, the underlying mechanisms are largely unknown. The present study was set to investigate effect of exercise training on age-induced cerebral microvascular alterations with modulation of VEGF and eNOS expressions. Male Wistar rats were divided into four groups: sedentary-young (4-6 months), sedentary-aged (21-22 months), immersed-aged (21-22 months) and trained-aged (21-22 months). Exercise program included swimming training 5 days/week for 8 weeks. Physiological characteristics including body weight, mean arterial blood pressure, plasma lipid profile and plasma malondialdehyde (MDA) level were determined. To investigation of microvascular networks of the brain, in situ study was performed for determining regional cerebral blood flow perfusion (rCBF) using a laser Doppler flowmeter and for visualizing the vasculature via cranial window, using a laser scanning confocal fluorescent microscope. Fluorescent images of the vasculature were recorded and off-line analyzed for capillary vascularity (CV) by using image analysis software. To examine possible underlying mechanism of exercise training on ameliorating cerebral vascular deterioration, VEGF and eNOS protein level in isolated brain microvessels were determined using immunoassay technique. We found that age induced significant alteration of these physiological characteristics in old rats when compared to those in young group. However, those parameters were significantly improved in trained-aged rats. In addition, CV and rCBF significantly reduced in non-exercise old rats when compared to those in young rats, however, in trained-aged rats, CV amd rCBF significantly elevated when compared to those in old rats without training. Further, age induced significant downregulation of VEGF and eNOS expression in aged rats when compared to those in young rats. In addition, exercise significantly upregulated VEGF and eNOS level in trained-aged rats when compared to those in non-exercise old rats. Moreover, the linear correlations between CV and either VEGF or eNOS levels were observed as well as a linear relationship between CV and plasma MDA level. Therefore, it implied that antioxidant effects of exercise training could protect brain microvascular and blood perfusion against aging, particularly associated with its actions on VEGF and eNOS expressions.