Graduation Date

Spring 5-6-2023

Document Type


Degree Name

Doctor of Philosophy (PhD)


Integrative Physiology & Molecular Medicine

First Advisor

Iraklis I. Pipinos

Second Advisor

George Casale

MeSH Headings

Peripheral Artery Disease, Microvessels


Background:Peripheral Artery Disease (PAD) is characterized by calf muscle fibrosis and myofiber oxidative damage (OxD). Our laboratory has demonstrated architectural changes of calf-muscle microvessels (

Methods:Gastrocnemius biopsies were collected from controls, patients with Stage II PAD, and Stage IV patients with limb-threatening ischemia. Carbonyl adducts (CA; oxidative damage), and Heme Oxygenase-1 (HO-1; anti-OxD in microvessels) were quantified in microvessels (

Results: Post-occlusive re-oxygenation of calf muscle was slowed in Stage II patients versus controls. Kinetic parameters correlated poorly with Ankle-Brachial Index. Microvessel CA was increased in pre- and post-exercise Stage II patients and in Stage IV patients versus controls and progressed with advancing disease. HO-1 abundance was higher in PAD versus controls but was not different among patient groups. Microvessel CA abundance (area x concentration) correlated strongly with myofiber CA abundance, in control muscle, whereas microvessel carbonyl concentration correlated strongly with myofiber CA abundance in pre- and post-exercise patients. Microvessel CA did not correlate with myofiber CA abundance in Stage IV patients. Nuclear HO-1 was strongly, inversely correlation with fibrosis in pre-exercise patients. With six months of exercise therapy, fibrosis increased and correlated positively with microvessel CA abundance. Neither microvessel CA nor HO-1 correlated with lower leg function.

Conclusions: Post-occlusive re-oxygenation kinetics and the association of microvessel and myofiber OxD implicate microvessels in the myopathy of PAD. Microvessel OxD worsens with advancing PAD and with exercise therapy. Microvessel nuclear HO-1 was anti-fibrotic under less extreme calf muscle OxD.

Available for download on Saturday, May 03, 2025