Effects of Leptin Signaling on Xenopus Tail Angiogenesis in Development and Regeneration

Grace H. Curtis

doi:10.7273/000007343

The role of leptin as a pro-angiogenic factor is well-established in multiple contexts in adult mammals, including wound healing. Additionally, leptin can act both at the local level of a wound and as a neuroendocrine signal. Prior research from our lab has shown that leptin increases the rate of regeneration in larval Xenopus laevis. However, it is currently unknown whether leptin acts as a pro-angiogenic factor during development and regeneration, and how leptin regulates regeneration via its different signaling pathways. This study demonstrates that leptin’s angiogenic role is conserved in peripheral tissues of developing and regenerating X. laevis, and explores multiple mechanisms through which leptin may promote regeneration and angiogenesis via local and neuroendocrine signaling pathways. In the first chapter, leptin is shown to promote peripheral angiogenesis during development. Leptin protein is expressed in and binds its receptor in developing blood vessels. Increased leptin signaling during the embryo-larval transition increases tail fin vessel length and development, while decreased leptin levels have an opposing effect and cause disorganization of tail vasculature and decrease of angiogenic gene expression. The second chapter demonstrates that leptin also promotes vascular regeneration. Local leptin expression increases regeneration rate and growth of regenerating blood vessels, while decreasing leptin reduces these. Gene expression analysis suggests that leptin regulates regeneration by promoting cell survival, inflammation, cell motility, ECM remodeling, metabolism, and cell proliferation. Leptin administration increases expression of genes that promote angiogenesis at the tissue and blood vessel level. Finally, the third chapter describes differences in vascular regeneration and gene expression due to local and systemic (i.e., neuroendocrine) leptin administration. Both physiological measurements and gene expression data show that both types of leptin administration accelerate tail regeneration and rate of angiogenesis into the blastema, but increased local leptin signaling caused an earlier increase in regeneration rate and vascular regeneration, while increased neuroendocrine leptin signaling via IP leptin injection had a later effect. Additionally, the function of gene clusters were similar between local and neuroendocrine leptin signaling, but the timing of this expression was affected by application method. This dissertation shows that leptin’s pro-angiogenic actions are conserved in models of development and regeneration, and that it modulates gene expression in multiple pro-regenerative pathways and affects the timing of responses based on application method. These results may have applications in the fields of wound treatment and regenerative medicine, identifying leptin as a potential therapeutic for angiogenic wound healing and a master regulator of development, wound healing, and regeneration.

Effects of Leptin Signaling on Xenopus Tail Angiogenesis in Development and Regeneration

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