Angiogenesis and vasculogenesis are impaired in the precocious-aging klotho mouse.
BACKGROUND
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.


RESULTS
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.


CONCLUSIONS
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.
Cardiovascular Research Institute, Kurume University, Kurume, Japan.
Toshifumi
T
Shimada
Yoshiaki
Y
Takeshita
Toyoaki
T
Murohara
Ken-ichiro
K
Sasaki
Kimiyasu
K
Egami
Satoshi
S
Shintani
Yosuke
Y
Katsuda
Hisao
H
Ikeda
Yo-ichi
Y
Nabeshima
Tsutomu
T
Imaizumi
D019588:Aging, Premature / Q000235:genetics / Q000503:physiopathology* / Q000628:therapy; D000818:Animals; D001013:Aorta, Thoracic; D016026:Bone Marrow Transplantation; D003097:Collateral Circulation / Q000235:genetics / Q000502:physiology*; D006152:Cyclic GMP / Q000032:analysis; D005966:Glucuronidase; D006614:Hindlimb / Q000098:blood supply / Q000000981:diagnostic imaging; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D007511:Ischemia / Q000000981:diagnostic imaging / Q000235:genetics / Q000503:physiopathology*; D000090265:Klotho Proteins; D017078:Laser-Doppler Flowmetry; D008565:Membrane Proteins / Q000172:deficiency* / Q000502:physiology; D051379:Mice; D008817:Mice, Mutant Strains; D023421:Models, Animal; D018482:Muscle, Skeletal / Q000737:chemistry; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000209:etiology*; D009566:Nitrates / Q000652:urine; D009569:Nitric Oxide / Q000378:metabolism; D009573:Nitrites / Q000652:urine; D009924:Organ Culture Techniques; D011725:Pyridines / Q000494:pharmacology / Q000627:therapeutic use; D014463:Ultrasonography
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008565:Membrane Proteins; D009566:Nitrates; D009573:Nitrites; D011725:Pyridines; D009569:Nitric Oxide; C086276:cerivastatin; D005966:Glucuronidase; D000090265:Klotho Proteins; D006152:Cyclic GMP