Faculty Collaboration Database

Adipose stromal vascular fraction reverses mitochondrial dysfunction and hyperfission in aging-induced coronary microvascular disease. Am J Physiol Heart Circ Physiol 2022 Oct 01;323(4):H749-H762

Date

08/27/2022

Pubmed ID

36018760

Pubmed Central ID

PMC9529257

DOI

10.1152/ajpheart.00311.2022

Scopus ID

2-s2.0-85139376250 (requires institutional sign-in at Scopus site)   3 Citations

Abstract

Aging is associated with blunted coronary microvascular vasodilatory function. Previously, systemically administered adipose stromal vascular fraction (SVF) therapy reversed aging-induced attenuation of β₁-adrenergic- and flow-mediated dilation dependent on reducing mitochondrial reactive oxygen species. We hypothesized that SVF-mediated recovery of microvascular dilatory function is dependent on recovery of mitochondrial function, specifically by reducing mitochondrial hyperfission. Female Fischer-344 rats were allocated into young control, old control, and old + SVF therapy groups. Pressure myography, immunofluorescent staining, Western blot analysis, and RNA sequencing were performed to determine coronary microvascular mitochondrial dynamics and function. Gene and protein expression of fission-mediator DRP-1 was enhanced with aging but reversed by SVF therapy. SVF facilitated an increase in fusion-mediator MFN-1 gene and protein expression. Mitochondrial morphology was characterized as rod-like and densely networked in young controls, isolated circular and punctate with aging, and less circularity with partially restored mitochondrial branch density with SVF therapy. Decreased mitochondrial membrane potential and ATP bioavailability in aged animals at baseline and during flow-mediated dilation were reversed by SVF and accompanied with enhanced oxygen consumption. Dilation to norepinephrine and flow in young controls were dependent on uninhibited mitochondrial fusion, whereas inhibiting fission did not restore aged microvessel response to norepinephrine or flow. SVF-mediated recovery of β-adrenergic function was dependent on uninhibited mitochondrial fusion, whereas recovery of flow-mediated dilation was dependent on maintained mitochondrial fission. Impaired dilation in aging is mitigated by SVF therapy, which recovers mitochondrial function and fission/fusion balance.NEW & NOTEWORTHY We elucidated the consequences of aging on coronary microvascular mitochondrial health as well as SVF's ability to reverse these effects. Aging shifts gene/protein expression and mitochondrial morphology indicating hyperfission, alongside attenuated mitochondrial membrane potential and ATP bioavailability, all reversed using SVF therapy. Mitochondrial membrane potential and ATP levels correlated with vasodilatory efficiency. Mitochondrial dysfunction is a contributing pathological factor in aging that can be targeted by therapeutic SVF to preserve microvascular dilative function.

Author List

Tracy EP, Nair R, Rowe G, Beare JE, Beyer A, LeBlanc AJ

Author

Andreas M. Beyer PhD Associate Professor in the Medicine department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Adenosine Triphosphate
Adipose Tissue
Adrenergic Agents
Animals
Female
Mitochondria
Norepinephrine
Rats
Rats, Inbred F344
Reactive Oxygen Species
Stromal Cells