Title : Oxidation of NO-receptor soluble guanylyl cyclase controls cerebral blood flow and cognitive function in mice
Abstract:
Decreased cerebral blood flow (CBF) is one of the major hemodynamic alterations leading to neurodegeneration and age-related cognitive decline. Nitric Oxide (NO)-dependent vasomotor reactivity is central in regulating cerebrovascular hemodynamics and adequate brain blood perfusion. NO receptor Soluble Guanylyl Cyclase (sGC) mediates NO-dependent vasodilation. Oxidative stress, often persisting in diseased vasculature, renders sGC insensitive to NO and impairs the NO signaling. The role of sGC oxidation in regulating CBF was never investigated. The present study investigated how sGC oxidation affects CBF and memory function in mice. To assess causal effect of sGC oxidation on NO signaling function we administered ODQ, a sGC-specific heme oxidizing agent, to simulate long-term effect of sGC oxidation in cerebral vasculature. Two groups of male mice (4 months old C57BL/6) were treated intraperitoneally (IP) twice a week for one month with ODQ (20 mg/kg, n=7) or a diluent as sham control (n=8). Changes in sGC-dependent cerebrovascular reactivity and memory function were assessed in both groups. We applied a non-invasive pulsed Doppler ultrasound-based system to assess the changes in blood flow velocity (PVF, % of baseline) in the mouse middle cerebral artery (MCA). MCA vasodilation was induced by bolus IP injection of NO donor sodium nitroprusside (SNP) or BAY 58-2667, a NO-independent activator of sGC with oxidized heme. Memory function was assessed by the Novel Object Recognition Task (NORT, RI, recognition index) in both experimental groups.
We observed a significantly blunted vasodilative response to SNP (1 mg/kg) in ODQ-treated mice vs controls (PVF, max response, 73.9 ± 10.4% vs 58.5 ± 8.6, p=0.01). The difference in BAY 58-2667 response between the groups was not statistically significant. The reduced memory function in ODQ-treated group was determined by NORT assessment (RI, 0.58 ± 0.13 vs 0.69 ± 0.05; p=0.01). Our results indicate that oxidation of NO receptor sGC in cerebral vasculature impairs CBF regulation and negatively affects memory function in mouse model. Our data suggests that sGC oxidation is an important contributor to cerebrovascular dysfunction and neurodegeneration.
Audience Take Away
- Audience will learn about new mouse model mimicking targeted oxidation of NO-receptor sGC enzyme
- The audience will discover the effect of sGC oxidation on regulation of cerebrovascular blood flow and memory function
- It will introduce the audience to a new potential mechanism of the disruption of CBF regulation by persistent oxidative stress and how it effects memory function
- Our presentation identifies a new molecular target for therapeutic interventions in conditions of neurodegeneration or age-related cognitive decline associated with oxidative stress
