Stromal Vascular Fraction Restores Vasodilatory Function by Reducing Oxidative Stress in Aging-Induced Coronary Microvascular Disease

Aims: The objective of this study is to identify mechanisms for adipose stromal vascular fraction's (SVF) restorative effects on vasodilation in aging-induced coronary microvascular disease (CMD). We hypothesize that reactive oxygen species (ROS) diminish beta 1-adrenergic receptor (beta 1ADR)- and flow-mediated dilation (FMD) in coronary arterioles, reversible by SVF and adipose-derived stem cells (ADSCs).Results: SVF attenuates aging-induced chronic accumulation of ROS and pro-oxidant gene and protein expression with enhancement of antioxidant gene and protein expression and glutathione, but not nitric oxide. ADSCs attenuate hydrogen peroxide while restoring nitric oxide and glutathione. Mass spectrometry of SVF- and ADSC-conditioned media reveals abundant antioxidant proteins suggesting a paracrine mechanism. FMD and beta 1ADR-mediated dilation diminished with aging, restored with SVF and ADSCs. FMD was restored by a switch in the acute signaling mediator from hydrogen peroxide in aging to peroxynitrite with SVF and ADSCs. Vasorelaxation to beta 1ADR-agonism was mechanistically linked with hydrogen peroxide, nitric oxide, and glutathione. Exogenous ROS eliminates isoproterenol-mediated dilation in youth that is blocked by inhibition of pro-desensitization and internalization proteins while nitric oxide enhances isoproterenol-mediated dilation in aging.Innovation: We introduce a novel mechanism by which ROS impacts beta 1ADR trafficking: the ROS/RNS-beta 1ADR desensitization and internalization axis. Aging-induced ROS shunts beta 1ADR from the plasma membrane into endosomes. SVF reduces oxidative burden, restoring functional beta 1ADR.Conclusions: SVF (and ADSCs to a lesser extent) reduce oxidative stress, and restore flow- and beta 1ADR-mediated vasodilation in aging. SVF represents a promising therapeutic strategy for CMD by addressing root cause of pathology; that is, oxidative stress-mediated hyperconstriction.

Automated summary

This study aimed to investigate the mechanisms underlying the restorative effects of adipose stromal vascular fraction (SVF) on vasodilation in aging-induced coronary microvascular disease (CMD). The results showed that SVF can attenuate chronic accumulation of reactive oxygen species (ROS) and enhance antioxidant gene and protein expression in coronary arterioles, thus restoring flow- and beta 1-adrenergic receptor (beta 1ADR)-mediated vasodilation. The study also identified a novel mechanism involving the impact of ROS on beta 1ADR trafficking.