Publication Date

2012-07-17

Availability

Open access

Embargo Period

2012-07-17

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PHD)

Department

Cancer Biology (Medicine)

Date of Defense

2012-06-25

First Committee Member

Enrique A. Mesri

Second Committee Member

Keith A. Webster

Third Committee Member

Zhao-Jun Liu

Fourth Committee Member

Theodore J. Lampidis

Abstract

PAD affects 7% of all people over 60 years of age, and 23% of all people over the age of 80. Over time, PAD progresses in severity, leading to critical limb ischemia (CLI), defined as an ankle-brachial index of 0.40 or less. Surgical bypass and other endovascular techniques are capable of providing temporary relief from symptoms of CLI in some subjects. However, recurrence of the disease is seen in over 30% of patients following surgical stent or graft intervention. As of yet there are no effective pharmacological agents available to treat CLI. Studies in this laboratory have defined a novel system using the mouse hindlimb model in which we can reproducibly promote recovery or failure of the vasculature following surgical ischemia. Using the mouse hindlimb model we have established conditions that promote full and partial recovery of limb perfusion, or failure of the therapy (and attendant limb loss). Adenoviral delivery of VEGF promotes an early burst of angiogenesis but does not support limb salvage. Adeno-associated virus-mediated VEGF delivery by a constitutive promoter supports limb salvage but is inferior to AAV that employs a hypoxia-regulated VEGF gene. My hypothesis is that ectopically administered VEGF can stimulate successful stable revascularization of ischemic muscle, provided a pro-angiogenic signaling gradient (directing endothelial tip cell migration via the Notch signaling pathway) is established. Unregulated VEGF expression or premature withdrawal causes the process to fail. Progression through this linear process will be defective qualitatively or quantitatively at one or more points when the therapy is inadequate.

Keywords

VEGF; ischemia; limb; gene therapy; arteriogenesis

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