Mechanisms for the Age‐Related Differences in Cerebral Artery Endothelial Function After Exposure to Elevated Pulse Pressure

Abstract

Greater large artery stiffness is correlated with increased cerebrovascular dysfunction and damage. One possible mechanism for this correlation is increased pulse pressure in cerebral resistance arteries, a result of less dampening of pulse pressure by the large arteries, leading to reduced cerebral artery endothelial function. Old age is associated with increases in large artery stiffness and cerebrovascular impairment; however, the effect of age on the response to elevated pulse pressure in cerebral arteries is unclear. Thus, we hypothesized that cerebral resistance arteries exhibit an age-related decline in endothelial function following exposure to pulsatile pressure. In young (n=41, 5-10 mo.) and old (n=26, 25-30 mo.) male C57BL6 mice, we measured cerebrovascular function by the ex vivo endothelium-dependent dilation (EDD) to acetylcholine (ACh) in isolated posterior cerebral arteries following exposure to static pressure (50 mmHg), low pulse pressure (50-75 mmHg), or high pulse pressure (37.5-87.5 mmHg)(400bpm). We also determined the effects of nitric oxide synthase inhibition (L-NAME) and decomposition of hydrogen peroxide (PEG-catalase) on the response to ACh. We measured endothelium-independent dilation (EID) by the dose response to sodium nitroprusside. We also measured posterior cerebral artery wall thickness in young and old mice using histological analysis. Compared with young mice, cerebral arteries from old mice had a 37.3% lower maximal EDD during exposure to static pressure (p<0.001), but EID did not differ with age (p=0.86). Exposure to low pulse pressure did not affect maximal EDD for either young or old cerebral arteries (p>0.05). In young cerebral arteries, maximal EDD was 43.9% lower after exposure to high pulse pressure compared with static pressure (p<0.005); however, high pulse pressure had no effect on maximal EDD in old cerebral arteries (p=0.39). Addition of L-NAME reduced maximal EDD in both old (p=0.001) and young (p<0.001) cerebral arteries during all pressure conditions, such that maximal EDD was no longer different between groups (p>0.05). In young cerebral arteries, the presence of PEG-catalase led to a lower maximal EDD in the static pressure (p=0.045) and low pulse pressure (p=0.001) conditions and trended towards greater maximal EDD in the high pulse pressure condition (p=0.08). Cerebral arteries from old mice had a 22% greater wall thickness compared with cerebral arteries from young mice (p=0.047). In conclusion, these results suggest high pulse pressure impairs endothelial function in cerebral resistance arteries from young mice, and this impairment results from lowered bioavailability of the products of nitric oxide synthase and reduced contribution by hydrogen peroxide to vasodilation. Contrary to our hypothesis, cerebral arteries from old mice were protected from the deleterious effects of high pulse pressure, perhaps as a result of arterial remodeling in response to chronic exposure to higher pulse pressure in vivo.