title: Impaired compensation to femoral artery ligation in diet-induced obese mice is primarily mediated via suppression of collateral growth by Nox2 and p47phox.
abstract: The present study was undertaken to establish the role of NADPH oxidase (Nox) in impaired vascular compensation to arterial occlusion that occurs in the presence of risk factors associated with oxidative stress. Diet-induced obese (DIO) mice characterized by multiple comorbidities including diabetes and hyperlipidemia were used as a preclinical model. Arterial occlusion was induced by distal femoral artery ligation in lean and DIO mice. Proximal collateral arteries were identified as the site of major (∼70%) vascular resistance to calf perfusion by distal arterial pressures, which decreased from ∼80 to ∼30 mmHg with ligation in both lean and DIO mice. Two weeks after ligation, significant vascular compensation occurred in lean but not DIO mice as evidenced by increased perfusion (147 ± 48% vs. 49 ± 29%) and collateral diameter (151 ± 30% vs. 44 ± 17%). Vascular mRNA expression of p22(phox), Nox2, Nox4, and p47(phox) were all increased in DIO mice. Treatment of DIO mice with either apocynin or Nox2ds-tat or with whole body ablation of either Nox2 or p47(phox) ameliorated the impairment in both collateral growth and hindlimb perfusion. Multiparametric flow cytometry analysis demonstrated elevated levels of circulating monocytes in DIO mice without impaired mobilization and demargination after femoral artery ligation. These results establish collateral resistance as the major limitation to calf perfusion in this preclinical model, demonstrate than monocyte mobilization and demarginatin is not suppressed, implicate Nox2-p47(phox) interactions in the impairment of vascular compensation to arterial occlusion in DIO mice, and suggest that selective Nox component suppression/inhibition may be effective as either primary or adjuvant therapy for claudicants.
authors: Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, Indiana; Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Indiana.
authors: Matthew R
authors: MR
authors: DiStasi
authors: Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana; Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Indiana.
authors: Julie A
authors: JA
authors: Mund
authors: Department of Cellular and Integrative Physiology, Indiana University School of Medicine, Indianapolis, Indiana;
authors: H Glenn
authors: HG
authors: Bohlen
authors: Department of Cellular and Integrative Physiology, Indiana University School of Medicine, Indianapolis, Indiana; Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana;
authors: Steven J
authors: SJ
authors: Miller
authors: Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana; Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana; and Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Indiana.
authors: David A
authors: DA
authors: Ingram
authors: Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana;
authors: Michael C
authors: MC
authors: Dalsing
authors: Department of Cellular and Integrative Physiology, Indiana University School of Medicine, Indianapolis, Indiana; Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana; junthank@iupui.edu.
authors: Joseph L
authors: JL
authors: Unthank
mesh_terms: D000098:Acetophenones / Q000494:pharmacology; D000222:Adaptation, Physiological; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D003097:Collateral Circulation; D003573:Cytochrome b Group / Q000235:genetics / Q000378:metabolism; D005263:Femoral Artery / Q000601:surgery*; D006614:Hindlimb / Q000098:blood supply; D008026:Ligation; D008562:Membrane Glycoproteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D000074662:NADPH Oxidase 2; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000235:genetics* / Q000378:metabolism; D018919:Neovascularization, Physiologic; D009765:Obesity / Q000378:metabolism*; D018384:Oxidative Stress; D012333:RNA, Messenger / Q000378:metabolism*
chemical_list: D000098:Acetophenones; D000975:Antioxidants; D003573:Cytochrome b Group; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; C056165:acetovanillone; C488842:Cybb protein, mouse; D000074662:NADPH Oxidase 2; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C422943:Nox4 protein, mouse; C515614:Cyba protein, mouse; C060505:neutrophil cytosolic factor 1
keywords: NADPH oxidase; Nox2; arteriogenesis; collateral resistance; vascular resistance