Impaired compensation to femoral artery ligation in diet-induced obese mice is primarily mediated via suppression of collateral growth by Nox2 and p47^phox

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.

Essential Role of IL-12 in Angiogenesis in Type 2 Diabetes

“…Recent evidence demonstrated that NADPH oxidases NOX2 and NOX4 were increased by an HFD. 23 Accordingly, real-time quantitative RT-PCR and Western blot analysis showed that Nox2 and Nox4 levels were upregulated in hind-limb muscles from WT mice fed an HFD but not in p40 À/À and p35 À/À mice fed an HFD (Figure 6, CeF). We could not detect Nox1 expression in ischemic limb muscle from all mice.…”

Vascular growth responses to chronic arterial occlusion are unaffected by myeloid specific focal adhesion kinase (FAK) deletion

“…Furthermore, adoptive transfer of Ly6C lo monocytes did not alter perfusion recovery or angiogenesis in contrast to adoptive transfer of Ly6C hi monocytes 38 41 . However, other studies have implied a role of the Ly6C lo monocyte population in both angiogenesis and arteriogenesis 42 43 44 45 .…”

Endothelial fluid shear stress sensing in vascular health and disease

“…Genetic mapping comparing the two strains at the extremes of the distribution for collateral arteriogenesis restrained the possible differences to a few genetic loci, though no candidate gene that explains the differences has been identified (102). Hypercholesterolemia (103,104), obesity (105), and aging (106) also compromise arteriogenesis in mouse models. Thus, poor flow-dependent remodeling in human arterial disease is likely to have multiple causes, potentially requiring personalized treatment.…”