Date on Master's Thesis/Doctoral Dissertation

5-2022

Document Type

Doctoral Dissertation

Degree Name

Ph. D.

Department

Physiology and Biophysics

Degree Program

Physiology and Biophysics, PhD

Committee Chair

LeBlanc, Amanda

Committee Co-Chair (if applicable)

Schuschke, Dale

Committee Member

Schuschke, Dale

Committee Member

Maldonado, Claudio

Committee Member

Metz, Cynthia

Committee Member

Hong, Kyung

Author's Keywords

Aging; microvascular; dysfunction; adrenergic; angiogenesis

Abstract

The role of the microcirculation is to balance blood flow and oxygen delivery to meet local metabolic and oxygen demands. With advancing age, the health of the endothelium declines leading to improper augmentation of the microcirculation; decreasing vasoreactivity and angiogenic potential which can further increase the risk of ischemia. The multiple contributing factors that drive the decline in endothelial health with age make traditional pharmacological interventions challenging whereas cell-based therapies can exert multifactorial gains. Adipose-derived stromal vascular fraction (SVF) is an emerging therapeutic for its easily accessible, autologous, anti-inflammatory, and angiogenic properties. It is a heterogenous population comprised of leukocyte and vascular cell populations as well as a small population of mesenchymal stem cells. Coronary perfusion and isolated coronary microvessels from young, old, and old treated with young SVF, female Fisher-344 rats were examined for health and functionality to beta-adrenergic receptor agonists (b-AR). Advancing age decreases coronary perfusion and vasoreactivity to b1-AR agonist norepinephrine (NE). A one-time tail vein injection of 10 million SVF cells 4 weeks prior reversed the age-related impairment in coronary microvascular dysfunction. Furthermore, isolated coronary microvessels from young, old, and old treated with SVF rats were examined for age- and SVF-related alterations in b1-AR cell signaling. Advancing age reduced the expression of b1-ARs on coronary microvessels and increased the expression of vasodilatory inhibitors, GRK2 and Gai. While SVF fully restored the b1-AR population it only marginally mitigated the inhibitor expression back to young control levels. Advancing age altered the cellular composition of SVF promoting a more pro-inflammatory phenotype with increased M1 macrophages and various types of T cells with a reduced mesenchymal stem cell population. Intravenously injected SVF can disseminate and engraft into the microcirculation of mesenteric windows; connective tissues located along the small intestines. SVF from young donors can significantly increase vascularized area of an aged mesenteric window subjected to a hypoxic-like injury compared to aged SVF which only marginally improves vascular area. Advancing age can drive a decline in the functionality of the microcirculation. SVF therapy offers a promising vascular therapeutic reversing the age-related dysfunction, increasing organ perfusion, and promoting revascularization following injury.

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