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 PS178. Supplemental Oxygen Reverses Hypoxia Induced Smooth Muscle Cell Proliferation by Modulating HIF-alpha and VEGF Levels in a Rabbit Arteriovenous Fistula Model

Jing Wan2, Charu Lata1, Ashley Santilli1, Derrick L. Green1, Sabita Roy1, Steven Santilli1
1Department of Surgery, Univ. of Minnesota, Minneapolis, MN; 2Zhongnan Hospital Wuhan University, Wuhan, China.

OBJECTIVES: Numerous mechanisms for the formation of intimal hyperplasia have been proposed, but none have been proven or accepted. Our research focuses on the potential role of hypoxia inducible factors (HIFs), VEGF and PDGF as well as the ERK, PI3-K/AKT pathway in hypoxia mediated intimal hyperplasia processes.
METHODS: Rabbits were randomized into different experimental groups with varying oxygen exposure and receipt of surgery. Plasma samples were collected at designated intervals in which cytokines and smooth muscle cell proliferation were measured. In addition, cell specimens were exposed to hyperoxic, normoxic and hypoxic environments with cytokines measured at various time points.
RESULTS: Placement of an arteriovenous fistula resulted in hypoxia induced HIF stabilization with a concurrent increase in VEGF. Activation of VEGF receptors on smooth muscle cells through ERK1 and AKT pathways resulted in significant smooth muscle cell proliferation and migration. These effects are dramatically reduced in animals that are exposed to a hyperoxic environment of 30% oxygen.
CONCLUSIONS: Our results suggest that short-term administration of supplemental oxygen inhibits HIFs and VEGF signaling to reduce smooth muscle proliferation in the local blood vessel. These results provide strong support for the therapeutic use of supplemental oxygen following arterial surgery to reduce intimal hyperplasia. These findings also provide a nidus for future studies into the mechanisms of hypoxia induced intimal hyperplasia.
AUTHOR DISCLOSURES: D. L. Green: Nothing to disclose; C. Lata: Nothing to disclose; S. Roy: Nothing to disclose; A. Santilli: Nothing to disclose; S. Santilli: Nothing to disclose; J. Wan: Nothing to disclose.
Posted April 2013

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