cyclic-gmp and Aging--Premature

The effects of aging on angiogenesis (vascular sprouting) and vasculogenesis (endothelial precursor cell [EPC] incorporation into vessels) are not well known. We examined whether ischemia-induced angiogenesis/vasculogenesis is altered in klotho (kl) mutant mice, an animal model of typical aging.. After unilateral hindlimb ischemia, laser Doppler blood-flow (LDBF) analysis revealed a decreased ischemic-normal LDBF ratio in kl mice. Tissue capillary density was also suppressed in kl mice (+/+>+/kl>kl/kl). Aortic-ring culture assay showed impaired angiogenesis in kl/kl mice, accompanied by reduced endothelium-derived nitric oxide release. Moreover, the rate of transplanted homologous bone marrow cells incorporated into capillaries in ischemic tissues (vasculogenesis) was lower in kl/kl mice than in wild-type (+/+) mice, which was associated with a decrease in the number of c-Kit+CD31+ EPC-like mononuclear cells in bone marrow and in peripheral blood. Finally, the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor cerivastatin restored the impaired neovascularization in kl/kl mice, accompanied by an increase in c-Kit+CD31+ cells in bone marrow and peripheral blood, and enhanced angiogenesis in the aortic-ring culture.. Angiogenesis and vasculogenesis are impaired in kl mutant mice, a model of typical aging. Moreover, the age-associated impairment of neovascularization might be a new target of statin therapy.

Topics: Aging, Premature; Animals; Aorta, Thoracic; Bone Marrow Transplantation; Collateral Circulation; Cyclic GMP; Glucuronidase; Hindlimb; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Ischemia; Klotho Proteins; Laser-Doppler Flowmetry; Membrane Proteins; Mice; Mice, Mutant Strains; Models, Animal; Muscle, Skeletal; Neovascularization, Pathologic; Nitrates; Nitric Oxide; Nitrites; Organ Culture Techniques; Pyridines; Ultrasonography