Analyses of Ca^<2+> signaling mechanisms of vascular and nerve formation using Ca^<2+> transporter-deficient mice

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The Na^+/Ca^2+ exchanger type-1 (NCX1) is considered to be involved in endothelial nitric oxide (NO) production. In this study, we examined the role of NCX1 in angiogenic response to acute hindlimb ischemia by using heterozygous NCX1 knockout (NCX1^<+/->) mice. Furthermore, since Lipo-PGE1 (prostaglandin El encapsulated into lipid microsphere) is well known as a useful drug for peripheral arterial disease, we examined the effect of Lipo-PGE1 in hindlimb ischemia-induced angiogenesis. We surgically induced unilateral hindlimb ischemia and monitored the blood flow recovery by Laser Doppler imaging for 4 weeks. Lipo-PGE1 treatment enhanced the blood flow recovery and capillary density in wild-type mice. Western blotting at 28 day showed that Lipo-PGE1 increased VEGF and phospho-Akt expression levels in the ischemic muscles. Interestingly, the blood flow recovery in NCX^<+/-> mice was significantly augmented compared with that in wild-type mice, although it was similarly enhanced by Lipo-PGE1 treatment. Moreover, to study possible involvement of endothelial NO synthase, we administered N^G-nitro-L-arginine methyl ester (L-NAME) to mice with hindlimb ischemia. L-NAME treatment eliminated the enhanced blood flow recovery observed in both NCX1^<+/-> mice and Lipo-PGE1-treated mice. These results suggest that NCX1, as well as Lipo-PGE1, is involved in endothelial NO synthase-dependent angiogenesis.