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Abstract 3: Mechanisms of Obesity-Related Lymphatic Dysfunction

Plastic and Reconstructive Surgery – Global Open: April 2016 - Volume 4 - Issue 4S - p 36
doi: 10.1097/01.GOX.0000488935.15892.b1
PRS PSRC Podium Proofs 2016

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Jessie Z. Yu, MD, Matthew D. Nitti, BA, Gabriela D. García Nores, MD, Geoffrey E. Hespe, BS, Jung-Ju Huang, MD, Raghu P. Kataru, PhD, Babak J. Mehrara, MD

From the Memorial Sloan Kettering Cancer Center, New York, N.Y.

PURPOSE: Lymphatic endothelial cell (LEC) function is regulated by the activation of VEGFR-3 by VEGF-C, and recent studies suggest that this signaling pathway is disturbed in obesity. Therefore, the purpose of this study was to develop a transgenic mouse model to selectively examine the effects of VEGFR-3 signaling in the lymphatic system and to use this model to understand how lymphatic defects modulate metabolic syndrome in obesity.

METHODS: To activate VEGFR-3 signaling in LECs independent of VEGF-C, we mated FLT4-Cre mice with PTEN-LoxP mice. Because FLT4 is an LEC-specific promoter, activation of Cre with tamoxifen results in knockout of PTEN, an intracellular inhibitor of VEGFR3, only in LECs thereby increasing the activation of VEGFR-3 downstream pathways. We used this model to analyze lymphatic function and metabolic parameters in a high-fat diet model of obesity.

RESULTS: PTEN knockout in LECs markedly increased lymphatic function in response to inflammation. More importantly, the loss of PTEN in obese mice significantly decreased the deleterious effects of obesity on the lymphatic system compared with controls. Moreover, even though PTEN knockout mice became obese when fed a high-fat diet, these mice were protected from metabolic syndrome and hepatic steatosis suggesting that lymphatic function is a significant regulator of these outcomes after weight gain.

CONCLUSIONS: We have shown that impaired VEGF-C/VEGFR-3 signaling in LECs is a major regulator of obesity-induced lymphatic dysfunction. More importantly, we have shown that increasing downstream signaling pathways of VEGFR-3 only in LECs significantly decreases metabolic syndrome and hepatic steatosis.

© 2016 American Society of Plastic Surgeons