Impaired Compensation to Femoral Artery Ligation in Diet Induced Obese Mice Is

24 This study was undertaken to establish the role of NADPH oxidase (Nox) in impaired vascular 25 compensation to arterial occlusion that occurs in the presence of risk factors associated with 26 oxidative stress. Diet-induced obese (DIO) mice characterized by multiple comorbidities 27 including diabetes and hyperlipidemia were utilized as a preclinical model. Arterial occlusion 28 was induced by distal femoral artery ligation in lean and DIO mice. Proximal collateral arteries 29 were identified as the site of major (~70%) vascular resistance to calf perfusion by distal arterial 30 pressures which decreased from ~80 to ~30 mm Hg with ligation in both lean and DIO mice. 31 Two weeks after ligation, significant vascular compensation occurred in lean but not DIO mice 32 as evidenced by increased perfusion (147±48 vs. 49±29%) and collateral diameter (151±30 vs. 33 44±17%). Vascular mRNA expression of p22, Nox2, Nox4, and p47 were all increased in 34 the DIO mice. Treatment of DIO mice with either apocynin or Nox2ds-tat, or whole-body 35 ablation of either Nox2 or p47, ameliorated the impairment in both collateral growth and 36 hindlimb perfusion. Multi-parametric flow cytometry analysis demonstrated elevated levels of 37 circulating monocytes in DIO without impaired mobilization and demargination after femoral 38 artery ligation. The results establish collateral resistance as the major limitation to calf perfusion 39 in this preclinical model, demonstrate than monocyte mobilization and demarginatin is not 40 suppressed, implicate Nox2-p47 interaction in the impairment of vascular compensation to 41 arterial occlusion in DIO mice, and suggest selective Nox component suppression/inhibition may 42 be effective as either primary or adjuvant therapy for claudicants. 43