Abstract
Background: We previously identified LOX-1 as a receptor for oxidized low-density lipoproteins. Recent studies show LOX-1 contributes to capillary formation induced by Angiotensin II or oxLDL, suggesting the potential effects of LOX-1 on angiogenesis. Therefore, we elucidated whether LOX-1 might be involved in angiogenesis in ischemic hindlimb tissue. Methods and Results: Ischemia was surgically produced by femoral artery ligature in both wild-type mice (WT) and LOX-1 deletion mice (LOX-1 KO). The ratio of ischemic/nonischemic leg blood flow measured by laser Doppler perfusion imaging was significantly smaller in LOX-1 KO than WT on Day 14, 21 and 28 (p<0.01). In agreement, histological capillary density (vWF immunostaining) was significantly lower in LOX-1 KO than in WT on Day 28 (115±28 vs. 177±19/HPF, p<0.01). Next, we analyzed phosphorylation of p38 involved in LOX-1 signaling. Phosphorylation of p38 was suppressed in ischemic hindlimb tissue of LOX-1 KO mice compared with WT mice. Western blot analyses also showed remarkable induction of VEGF in hindlimb of WT on Day 3 after ischemia. On the other hand, ischemic tissues of LOX-1 KO contained very low VEGF, resulting in suppressed phospholylation of Akt and eNOS, which are downstream signaling of VEGFR2. Considering the fact that inflammation is important for ischemia-induced angiogenesis, we examined whether infiltrated macrophages (F4/80 immunochemistry) release VEGF in ischemic hindlimb using two-color immunofluorescence histochemical staining. Fewer numbers of macrophages infiltrated into the ischemic tissues in LOX-1 KO than in WT (64±24 vs. 118±25/HPF, p<0.01), and immunohistochemical analysis revealed the number of infiltrated macrophages expressing VEGF was also decreased in LOX-1 KO (LOX-1: 34±19 vs. WT: 50±14/HPF, p<0.01). Conclusions: This study demonstrates that LOX-1 deletion negatively modulates ischemia-induced angiogenesis through impairment of early inflammatory mononuclear cell infiltration, which releases VEGF. LOX-1 would become a novel target molecule for modulating angiogenesis in ischemic tissue.
Published Version
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