Pulse pressure-dependent cerebrovascular eNOS regulation in mice

Abstract

Arterial blood pressure is oscillatory; whether pulse pressure (PP) regulates cerebral artery myogenic tone (MT) and endothelial function is currently unknown. To test the impact of PP on MT and dilation to flow (FMD) or to acetylcholine (Ach), isolated pressurized mouse posterior cerebral arteries were subjected to either static pressure (SP) or a physiological PP (amplitude: 30 mm Hg; frequency: 550 bpm). Under PP, MT was significantly higher than in SP conditions (p < 0.05) and was not affected by eNOS inhibition. In contrast, under SP, eNOS inhibition increased (p < 0.05) MT to levels observed under PP, suggesting that PP may inhibit eNOS. At a shear stress of 20 dyn/cm 2 , FMD was lower (p < 0.05) under SP than PP. Under SP, eNOS-dependent O À 2 =H 2 O 2 production contributed to FMD, while under PP, eNOS-dependent NO was responsible for FMD, indicating that PP favours eNOS coupling. Differences in FMD between pressure conditions were abolished after NOX2 inhibition. In contrast to FMD, Ach-induced dilations were higher (p < 0.05) under SP than PP. Reactive oxygen species scavenging reduced (p < 0.05) Ach-dependent dilations under SP, but increased (p < 0.05) them under PP; hence, under PP, Ach promotes ROS production and limits eNOS-derived NO activity. In conclusion, PP finely regulates eNOS, controlling cerebral artery reactivity.

Matched increases in cerebral artery shear stress, irrespective of stimulus, induce similar changes in extra-cranial arterial diameter in humans

“…In animals, classic studies have established that increases in flow and shear stress through isolated cerebral conduit arteries trigger endothelial-mediated vasodilation. 16 Recently, Raignault et al 17 illustrated that the cerebrovascular endothelium optimally couples shear stress to eNOS-mediated dilation under physiological pulse pressures, in contrast to static flow conditions. This strongly infers that changes in cerebral arteries are responsive to a pulsatile environment and that shear stress sensitivity and consequent production of NO are optimised under in vivo conditions.…”

Systolic hypertension-induced neurovascular unit disruption magnifies vascular cognitive impairment in middle-age atherosclerotic LDLr−/−:hApoB+/+ mice

“…The artery segment was equilibrated for 45 min, allowing for myogenic tone to develop. Because myogenic tone is very low in cerebral arteries from C57Bl/6 mice (Raignault et al 2017), arteries were pre-constricted to~25% of the initial diameter with phenylephrine (Sigma-Aldrich; 1 μmol/L) after equilibration and myogenic tone development, as previously reported (Raignault et al 2017); then, dilatory responses were tested with a single cumulative concentration response curve to acetylcholine (Ach, Sigma-Aldrich; 10 −13 mol/L to 10 −4 mol/L). Responses to Ach were expressed as percentage of change in vessel diameter from pre-constriction tone.…”

Cerebral and skeletal muscle feed artery vasoconstrictor responses in a mouse model with greater large elastic artery stiffness

“…It is also important to consider the role of autoregulation by cerebral resistance arteries in maintaining constant cerebral blood flow (Mitchell, 2008). The greater pressure pulsatility associated with increased large elastic artery stiffness might result in myogenic vasoconstriction of cerebral resistance arteries (Raignault, Bolduc, Lesage, & Thorin, 2017), an effect that might be additive with the greater Ang II responsiveness.…”