Deficiency of Senescence Marker Protein‐30 Impairs Collateral Growth by Supressing Nitric Oxide Bioactivity under Ischemia

Abstract

Aging impairs collateral growth under ischemia and reduces the expression of VEGF, however the exact mechanism is unclear. Senescence marker protein‐30 (SMP30) decreases with aging. Mice with SMP30 deficiency, a model of aging, have a short lifespan with increased oxidant stress. To elucidate the effect of SMP30 on ischemia‐induced collateral growth, we examined the recovery of cutaneous blood flow (CBF) after femoral artery ligation by laser Doppler imaging in mice. Recoveries of CBF and tissue capillary density were suppressed in SMP30 knockout (KO) mice compared to those of wild type (WT) mice. Acetylcholine (ACh, 1 µM)‐induced NO generation in aorta of SMP30 KO mice was lower than those of WT mice. Superoxide generation and NADPH oxidase activity were greater in aorta of SMP30 KO mice compared to that of WT mice (superoxide level: 3.3±0.5 vs. 1.6±0.2 nmol/mg protein; NADPH oxidase activity: 3240±254 vs. 982±106 RLU; P<0.01, respectively). VEGF content in the biceps femoris muscle in SMP30 KO mice did not increase in 14 days post‐ischemia compared to that in pre‐ischemia (SMP30 KO mice 1.1±0.2 fold vs. WT mice 2.2±0.3 fold, P<0.01). Akt phosphorylation in the biceps femoris muscle was attenuated in SMP30 KO mice compared to that of WT mice (p‐Akt/Akt: SMP30 KO mice 0.4±0.3 vs. WT mice 1.2±0.4, P<0.01). Thus, SMP30 deficiency exacerbates oxidant stress due to NADPH oxidase activation and impairs eNOS activity, which leads to rarefaction of collateral growth induced by ischemia related to Akt‐VEGF pathway. These results suggest that the decrease of SMP30 in aging impairs VEGF/NO‐dependent angiogenesis associated with overproduction of superoxide.