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Pellino 1 Gene Therapy Shows Novel Proangiogenic Function by Improving Survivability of Ischemic Skin Flap Tissue in Flk-1 Knockout Mice via NO/HO-1 Signaling Cascade
*Rickesha L Wilson1, *Chandra K Rednam2, *Vaithinathan Selvaraju1, *Muhammad T Rishi2, *Mahesh Thirunavukkarasu1, J.Alexander Palesty2, David W McFadden1, *Nilanjana Maulik1
1University of Connecticut Health, Farmington, CT;2Saint Mary's Hospital, Waterbury, CT

Objective: The aim of this study is to elucidate for the first time the role of Pellino 1 (Peli1) in neovascularization and skin flap survival.
Design: This study uses a preclinical murine ischemic skin flap model. Animals were divided into three experimental groups: WT, Flk-1 +/-, and Flk-1+/- + Ad.Peli1. Mice in each group underwent dorsal ischemic skin flap surgery. Follow up was up to 12 days after surgery.
Setting: Molecular Cardiology and Angiogenesis Laboratory, University Research Facility.
Patients: WT and Flk-1+/- mice were studied.
Interventions: Peli1 was transfected into an adenoviral vector (Ad.Peli1) and injected locally around the skin flap as a therapeutic intervention in Flk-1+/- mice.
Main Outcome Measures: Blood perfusion to the skin flap area, extent of necrosis, capillary density, and HO-1 expression.
Results: Laser Doppler imaging demonstrated vastly improved perfusion in Flk-1+/- + Ad.Peli1 mice compared to Flk-1+/- mice and WT mice, (n=8-10), p < 0.05. Extent of necrosis quantified by digital imaging on postoperative days 4, 8, and 12 was drastically reduced in Flk-1+/- + Ad.Peli1 mice compared to Flk-1+/- mice but not WT mice, (n=8-13). Caveolin-1 staining was performed in postoperative day 12 tissue samples and revealed a large increase in capillary percentage in Flk-1+/- + Ad.Peli1 mice compared to Flk-1+/- mice but not WT mice, (n=4-6), p < 0.05. HO-1 staining in postoperative day 12 tissues in Flk-1+/- + Ad.Peli1 mice showed much higher HO-1 expression compared to Flk-1+/- mice but similar to WT mice, (n=4-6), p< 0.05.
Conclusions: Peli1 gene therapy powerfully restores impaired angiogenesis and enhances skin flap survival in mice, potentially offering surgeons a promising therapeutic agent to improve surgical and cosmetic outcomes.


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