Graduation Date

Spring 5-4-2024

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Programs

Molecular Genetics & Cell Biology

First Advisor

Hanjun Wang

MeSH Headings

Peripheral Artery Disease, Hindlimb Ischemia, Neuroinflammation

Abstract

Peripheral arterial disease (PAD) is a progressive and debilitating atherothrombotic disorder that is estimated to impact >200 million people worldwide. Higher physical activity levels are associated with better overall survival rates, slower decline of functional capability, and improved quality of life. However, intermittent claudication, pain produced by physical activity, severely limits functional capacity in PAD patients. Despite known sensory dysfunction and documented neuropathy in diseased patients, the neural mechanisms that produce pain in PAD are yet to be identified. Importantly, few animal models of hindlimb ischemia (HLI) successfully recapitulate chronic human PAD. We developed a chronic animal model of HLI using intra-femoral catheter occlusion (IFCO). We found that IFCO persistently reduced blood flow to the hindlimb and produced PAD-associated myopathy, including fibrosis and a reduction in cross-sectional area. Using IFCO, a previous pilot study found increased pro-inflammatory macrophage infiltration and activation within the lumbar dorsal root ganglia (DRGs) at the chronic stage of HLI, not only indicating neural inflammation but also the potential for temporally dimorphous mechanisms of pain. We next devised a new tissue-clearing method to analyze the time-dependent effects of HLI on the organization of sensory nerves and vasculature. Surprisingly, only the sciatic nerve had patent alternations in sensory nerve organization. As expected, capillary networks were severely damaged during the acute stages of IFCO but rebounded chronically to levels significantly higher than baseline. Finally, because pro-inflammatory macrophages are sources of reactive oxygen species and pro-inflammatory cytokines, we sought to investigate whether nuclear factor erythroid 2-related factor (Nrf2), a transcription factor coordinating cellular antioxidative responses, in sensory neurons could protect against ischemia-induced pain. We found that upregulating Nrf2 in a subset of sensory neurons that express the transient receptor potential vanilloid 1 (TRPV1) receptor increased mechanical thresholds, indicating that Nrf2 prevented mechanical hypersensitivity. Collectively, this work demonstrates that IFCO is a reproducible and efficient method for studying HLI in rodents and that Nrf2 signaling is a component of sensory dysfunction and pain.

Comments

2024 Copyright, the authors

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