CYB5R3 BIASES SOLUBLE GUANYLYL CYCLASE ACTIVATION IN RESISTANCE ARTERIES

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Objective: Nitric oxide (NO) regulates blood pressure by binding the reduced heme iron on soluble guanylyl cyclase (sGC) in vascular smooth muscle cells (SMC) which leads to the production of cyclic guanosine 3’,5’-monophosphate (cGMP) and vasodilation. In cardiovascular disease, oxidative stress causes oxidation or loss (apo-) of the sGC heme, impairing NO binding and causing vasoconstriction. Subsequently, new therapeutic compounds termed sGC activators have been developed for use in cardiovascular disease to target oxidized heme, and to a greater extent apo-sGC, to cause irreversible, NO-independent reactivation of cGMP production and vasodilation. However, few studies have defined the impact of NO-independent sGC activation on vascular physiology in non-stressed conditions. Design and method: To address this, we performed vasoreactivity studies on resistance and aortic arteries under non-stressed, physiological conditions and telemetry for in vivo blood pressure recordings. Results: Interestingly, we found that resistance arteries are log-orders more sensitive to sGC activator BAY 58–2667 than conduit aortic arteries in non-stressed conditions. This suggests that resistance arteries may contain a previously unknown, physiologically activatable pool of heme oxidized and/or apo-sGC that can be activated independent of NO and disease. We have previously published that cytochrome b5 reductase 3 (CYB5R3) reduces the oxidized heme sGC to its NO-sensitive, reduced state which confers resilience from systemic hypertension. We hypothesized that CYB5R3 may serve as a rheostat in physiological blood pressure and sGC activator function. In transgenic CYB5R3 overexpression (CYB5R3 OE) mice, we found that resistance arteries, but not aorta have a blunted response to sGC activator induced vasodilation and blood pressure lowering in unstressed conditions (n = 4–8/group). OE CYB5R3 mice also exhibit a ∼7 mmHg decreases in pulse pressure and impaired blood pressure reduction in response to an acute injection of BAY 58–2667 when compared to controls (n = 5/group). Consistent with this, no difference in vasodilation response to NO donor sodium nitroprusside (SNP) was observed between CYB5R3 OE and littermate controls irrespective of vessel type (n = 2–6/group). Conclusions: These data suggest that CYB5R3 is important in regulating resistance artery sensitivity to sGC activator BAY 58–2667 likely via governing sGC redox state in non-stressed, physiological conditions.