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Gender-specific Differences in Tissue Remodeling and Revascularization Following Gene-based Therapy in a Mouse Model of Hind Limb Ischemia
Priscilla E. Lam*1, Mahesh Thirunavukkarasu2, Ajayan Manoor Supran2, Pradeep Seetur Radhakrishna2, Andrew Kemerley2, Alexander Palesty1, Nilanjana Malik2
1Surgery, Saint Mary's Hospital, Waterbury, CT; 2Surgery, University of Connecticut School of Medicine, Uconn Health, Farmington, CT


1. Objective: We previously reported that the Pellino-1 (Peli1) protein, a ubiquitin E3 ligase, can improve the pro-angiogenic response in ischemic tissues. This study aims to show gender-based differences in revascularization and outcomes following Peli1 gene therapy in the hind limb ischemia model.
2. Design: Experimental animal study.
3. Setting: University-affiliated academic research lab.
4. Patients: Not applicable.
5. Interventions: 8-12-week-old male and female CD1 mice underwent right hind limb femoral artery ligation and subsequent treatment with either intramuscular adenovirus injection carrying the Peli1 gene (Ad.Peli1, 1x10^9PFU in 50 μl of phosphate buffered saline [PBS]) or LacZ gene (Ad.LacZ, 1x10^9PFU in 50 μl PBS).
6. Main Outcome Measures: Lower limb perfusion was measured bilaterally in all animals preoperatively and postoperatively at defined time points through post-op day 28 using Laser Doppler Imaging (LDI). Perfusion ratios were calculated by comparing the region of interest (ROI) of the nonischemic to the ischemic limb. Post-mortem tissue collection of hind limb muscles for immunohistochemical (IHC) analysis to determine the extent of fibrosis, capillary density and vascular endothelial growth factor (VEGF) expression was also performed.
7. Results: Regardless of gender, Ad.Peli1 treated groups [Male: Ad.LacZ= 0.20 "0.02 (n=13) vs. Ad.Peli1= 0.53 "0.04 (n=15), p<0.0001; Female: Ad.LacZ= 0.19 "0.01 (n=14) vs. Ad.Peli1= 0.32 "0.04 (n=12), p=0.01] demonstrated a significant difference in perfusion at 28 days following HLI when compared to their gender-matched counterparts treated with Ad-LacZ. When directly comparing male and female Ad.Peli1 treatment groups, there was reduced perfusion efficiency in females compared to male treated groups (p=0.0006). IHC analysis revealed that mice treated with Ad.Peli1 demonstrated more robust VEGF expression and decreased fibrosis [Male: Ad.LacZ= 18.57 "1.09% vs. Ad.Peli1= 12.30 "1.56%, p=0.03; Female: Ad.LacZ= 45.58 "1.13% vs. Ad.Peli1 = 29.09 "5.12%, p=0.0004]; compared to their gender-matched counterparts. Female mice developed more fibrosis in the treatment group compared to the male-treated and male LacZ-treated groups, despite having an improved perfusion ratio compared to male Lac-Z treated mice.
8. Conclusions: Treatment with Ad-Peli1 increases perfusion and VEGF expression in both male and female mice when compared to gender-matched controls after HLI surgery. Despite improvement in functional recovery and perfusion, male Ad-Peli1-treated mice showed better recovery than their female counterparts. There is a need for increased awareness and further research into gender-specific responses to therapy.


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