The Role of Endothelial FoxO Proteins in Coordinating Skeletal Muscle Recovery Following Hind Limb Ischemia

Abstract

Muscle regeneration requires inflammation followed by microvascular growth and blood-flow recovery; however, these are impaired in ischemic muscle of peripheral artery disease patients. Endothelial cell (EC)-specific Forkhead Box O (FoxO) 1 and 3 proteins are known to influence vascular growth. My thesis aimed to elucidate their contributions to regeneration of ischemic muscle. I hypothesized that depleting both EC-FoxO1 and 3 (EC-FoxO1,3-knockdown (KD)) would most effectively enhance inflammatory resolution, blood flow recovery, microvascular growth and skeletal muscle regeneration following hind-limb ischemia, compared to EC-FoxO1-knockdown (KD) or EC-FoxO1,3-expressing (Control) mice. My results revealed EC-FoxO1,3-KD mice had enhanced post-ischemic microvascular growth, blood flow recovery, myofiber maturation and fibrosis compared to Control and EC-FoxO1-KD mice. Therefore, EC-FoxO1 and 3 depletion can improve multiple aspects of ischemic muscle recovery; highlighting novel roles of EC-FoxO proteins. Ultimately, my thesis provides insight into a potential therapeutic target for the better management of ischemic muscle outcomes.