Klotho gene product may have a role to regulate VEGF and p21 and tightly linked to the endothelial function to release NO

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A novel murine model of aging (kl/kl mice) was developed by in vivo mutagenesis. We investigated the endothelial function in this strain. Ring preparations of the thoracic aorta were obtained from wild-type (+/+), heterozygous (+/kl) and homozygous (kl/kl) mice for the transgene at age 6 to 9 weeks. The aorta of kl/+ mice showed an exaggerated contractile response to norepinephrine and attenuated vasodilator responses to acetylcholine and lecithinized superoxide dismutase (SOD) as compared with those of +/+ mice. The reseponse to sodium nitroprusside was unaltered. The contraction to norepinephrine was augmented by treatment with N^G-nitro-L-arginine methyl ester (LNAME) 10^<-5> M, more so in +/+ mice than in kl/+ mice. The treatment with LNAME abolished the vasodilator responses to both acetylcholine and lecithinized SOD.NO metabolites (NO_2^- and NO_3^-) and cyclic GMP in urine were significantly reduced in kl/+ mice compared with +/+ mice. However, urinary excretion of 6-keto prostaglandin F1α was unaltered. Immunostaining of NO synthase and vascular endothelial growth factor (VEGF) was low and immunostaining of cell cycle-dependent kinase inhibitor p21 was elevated in the aorta of kl/+ mice. No immunostaining of NO synthase was noted in the aorta of kl/kl mice.Klotho gene product may have a role to regulate VEGF and p21, protect endothelial cells from cellular senescence and tightly linked to the endothelial function to release NO.