Aerobic exercise prevents rarefaction of pial collaterals and increased stroke severity that occur with aging

Abstract

Variation in extent of the brain's collateral circulation is an important determinant of variation in the severity of stroke and efficacy of revascularization therapies. However, the number and diameter of pial collateral "arterioles" decrease with aging in associated with reduced eNOS and increased oxidative stress. We tested whether exercise reduces this aging-induced rarefaction. Twelve-month-old mice were randomized to sedentary or voluntary wheel-running. At 26 months' age, permanent MCA occlusion was followed 72 h later by determination of infarct volume and vascular casting after maximal dilation. The decline in collateral number and diameter and 2.4-fold increase in infarct volume evident in 26-versus 3-month-old sedentary mice were prevented by exercise-training. In contrast, number and diameter of the posterior communicating collateral "arteries" were unaffected by aging or exercise. Interestingly, diameter of the primary intracranial arteries increased with aging. Mechanistically, genetic overexpression of eNOS inhibited age-induced collateral rarefaction, and exercise increased eNOS and SOD2 and decreased the inflammatory marker NFkB assessed in hindlimb arteries. In conclusion, exercise prevented age-induced rarefaction of pial collaterals and reduced infarct volume. Aging also promoted outward remodeling of intracranial arteries. These effects were associated with increased eNOS and reduced markers of inflammation and aging in the vascular wall.

Mouse models of Alzheimer’s disease cause rarefaction of pial collaterals and increased severity of ischemic stroke

“…B6.CX 3 CR 1 −/− were B6.129P(Cg)-Ptprc a Cx3cr1 tm1Litt /LittJ. B6.eNOS transgenic mice have a twofold increase in NO production [ 32 ]. Approximately, equal numbers of males and females were studied in each experiment.…”

“…In a previous study, the observed effects of sex were negligible for native pial collateral number, diameter, and amount of rarefaction seen with aging in 3.5-, 8-, and 22-month-old B6 mice or 8 versus 18-month-old B6; 129SvEv mice [ 43 ]. Angiography was performed after perfusion-fixation at maximal dilation and filling of the pre-capillary vessels with viscosity-adjusted Microfil ® [ 32 ]. All pial collaterals between the ACA and MCA trees of both hemispheres were identified and their anatomic (maximally dilated) lumen diameters were measured at midpoint and averaged for each animal.…”

“…All pial collaterals between the ACA and MCA trees of both hemispheres were identified and their anatomic (maximally dilated) lumen diameters were measured at midpoint and averaged for each animal. Collateral length, tortuosity, calculated relative resistance of the MCA-to-ACA collateral network, territories of the ACA, MCA, and PCA trees, and other morphometrics were also measured [ 23 , 32 ]. Number and average diameter of the penetrating arterioles (PAs) diverging from the collaterals and branches of the ACA tree overlying the dorsal cortex were measured after optical clearing.…”

“…Environmental factors also affect collateral extent. Aging, hypertension, diabetes, endothelial dysfunction, and other vascular risk factors cause a decline or pruning away of collaterals and a smaller lumen diameter in those that remain (collateral rarefaction) [ 29 – 32 ]. Indirect measures of collaterals assessed during the hyperacute stage of stroke indicate that collateral conductance also varies widely in humans and is adversely affected by vascular risk factors [ 21 , 22 , 33 – 35 ].…”

“…Indirect measures of collaterals assessed during the hyperacute stage of stroke indicate that collateral conductance also varies widely in humans and is adversely affected by vascular risk factors [ 21 , 22 , 33 – 35 ]. The cause of this risk factor-induced rarefaction of collaterals, which does not occur in other pial vessels [ 29 , 31 ], has been suggested to extend from a unique sensitivity of collaterals, created by the low and disturbed shear stress and high wall stress normally present in them, to diseases and conditions that increase oxidative stress and inflammation [ 29 – 32 ]. Of note, traditional vascular risk factors also increase the risk of, or are strongly associated with, AD and vascular cognitive impairment [ 3 , 7 , 36 – 39 ].…”