Graduation Date

Summer 8-19-2016

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Programs

Cellular & Integrative Physiology

First Advisor

Iraklis Pipinos

Second Advisor

George Casale

Abstract

Peripheral Artery Disease (PAD) affects over 200 million people worldwide with a 5-year mortality rate as high as 30%. Atherosclerotic blockages impair blood flow to the lower limbs, causing ischemic leg pain and dysfunction upon exercise that later progresses to ulcerations and gangrene and often requires amputation. The standard therapies, revascularization and exercise, allow patients to walk further and longer but are at best maintained short-term. One explanation may be the development of myopathic changes in the limb that progress despite improved hemodynamics—a paradigm shift in the classic view of PAD pathophysiology as solely a mismatch between blood supply and demand. Thus, it is imperative that we characterize aspects of this myopathy, identify their functional consequences, and determine how their development is affected by standard therapies. Such knowledge is critical to developing adjunct therapeutic strategies that directly target the myopathy to improve the limb function of PAD patients. Excessive extracellular matrix deposition, or fibrosis, causes end-organ dysfunction in cardiovascular diseases. In the gastrocnemius of PAD patients, we have localized increased expression of a key pro-fibrotic cytokine Transforming Growth Factor-Beta 1 (TGF-β1) to microvessels and demonstrated a direct relationship with collagen deposition through advancing disease stages of PAD. We determined that vascular smooth muscle cells and not macrophages, T cells, fibroblasts, or endothelia, are the primary producers. We also demonstrated an inverse relationship between vascular TGF-β1 expression and hemodynamics, which suggests that local ischemia-hypoxia may induce TGF-β1 expression. Our study of PAD patients with unilateral disease confirmed that TGF-β1 dependent myofibrosis is a localized response in the ischemic muscle without significant systemic contributions. Collectively, the data suggest that the development of myofibrosis in PAD is of a vascular etiology. To determine how myofibrosis is affected by standard therapies, patients either underwent revascularization, supervised exercise therapy, or received no interventions for 6 months. Biopsies and limb function measurements were obtained at baseline and 6 months. Without intervention, myofibrosis progressed in the gastrocnemius of PAD patients but did not alter limb function. Patients in the exercise group had increased myofibrosis despite improved limb function. However, myofibrosis did not progress in patients who underwent revascularization. These data suggest that long term benefits to the lower limb of PAD patients are better with revascularization than exercise by preventing myofibrosis progression. Moreover, benefits of exercise on limb function are not due to alterations in myofibrosis. Overall, the findings validate the need for adjunct therapies that directly decrease TGF-β1 expression, given that neither revascularization nor exercise reverses myofibrosis in PAD patients.

Available for download on Monday, July 16, 2018

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