Targeting Endogenous Antioxidant Capacity to Prevent Vascular Dysfunction Induced by Limb Immobilization
Authors: Fermoyle Caitlin , Lewis Matthew , Craig Jesse , McKenzie Alec , Richardson Russell , Trinity Joel 
Published: May 2022

Background

Brief periods of limb disuse that accompany orthopedic injuries can impair vascular function and increase cardiovascular disease risk. Specifically, limb immobilization elicits a decrease in vascular shear stress which leads to an increase in oxidative stress and impaired vasodilation. We hypothesized that increasing the activation of nuclear factor‐erythroid factor 2‐related factor 2 (Nrf2), a critical transcription factor that regulates expression of endogenous antioxidants, using a novel, naturally occurring, supplement (PB125), would preserve vascular function during 14 days of limb immobilization.

Methods

Ten young, healthy individuals were randomized to receive either PB125 (100mg, N=6, 3M/3F, 28±5 y, BMI= 25±6 kg/m2) or placebo (N=4, 1M/3F, 23±4 y, BMI=24±3 kg/m2). Utilizing Doppler ultrasound, before and after 14 days of leg immobilization, leg blood flow (LBF) and vascular conductance (LVC) were measured in the common femoral artery at rest and during passive leg movement (PLM), and during knee‐extensor (KE) exercise at 3 relative intensities (40, 60, 80% of max; KE max = 35±10W). Additionally, flow mediated dilation (FMD) and post‐occlusive reactive hyperemia were assessed in the popliteal and brachial arteries.

Results

Lower limb immobilization reduced daily step count by 53 ± 19% in both groups (PB125 vs. placebo p > 0.05). Femoral, popliteal, and brachial artery diameters were not significantly different following immobilization. Resting LBF and LVC were lower following immobilization in the placebo group (pre vs. post; LBF: 485±124 vs. 357±106 ml/min, p = 0.001; LVC: 5.2±1.1 vs. 3.7±0.9 ml/min/mmHg, p = 0.001), but were preserved in the PB125 group (LBF: 239±63 vs. 237±78 ml/min, p > 0.05; LVC: 2.6±0.6 vs. 2.6±0.7 ml/min/mmHg, p > 0.05). However, LBF and LVC during KE exercise were not impacted by limb immobilization. Microvascular function, as assessed by the hyperemic response to PLM, was diminished in the placebo group (LVC Δpeak: 6.8±2.8 vs. 3.7±1.4 ml/min/mmHg, p = 0.049), but preserved in the PB125 group (LVC Δpeak: 3.0±0.6 vs. 3.0±1.8 ml/min/mmHg p > 0.05). Conversely, microvascular function, assessed by reactive hyperemia, was unchanged in both the popliteal and brachial arteries. Macrovascular function changes due to immobilization were limb‐specific, with a decrease in popliteal artery FMD with placebo (6.5±4.1 vs. 1.9±1.6 %, p = 0.046) and preservation with PB125 (4.4±3.6 vs. 2.8±1.9 %, p > 0.05), while brachial artery FMD was unchanged in both groups (p > 0.05).

Conclusions

Limb immobilization induced both microvascular and macrovascular changes in the leg which may contribute to the attenuated LBF and LVC at rest. Administration of PB125 preserved vascular function during disuse, presumably by mitigating the deleterious impact of oxidative stress. Hence, PB125 supplementation, and, therefore, augmented endogenous antioxidant capacity, appears to mitigate the negative vascular effects of limb disuse.