August 10, 2004Open Access
View Full PaperAngiogenesis and Vasculogenesis Are Impaired in the Precocious-Aging klotho Mouse
Key Result
In klotho mutant mice, ischemia-induced angiogenesis and vasculogenesis are impaired compared to wild-type mice, but neovascularization can be restored by treatment with cerivastatin.
Structured PICO
Does cerivastatin improve impaired angiogenesis and vasculogenesis in the precocious-aging klotho mouse model?
P
Population
klotho (kl) mutant mice (kl/kl and +/kl), an animal model of typical aging, and wild-type (+/+) mice subjected to unilateral hindlimb ischemia
I
Intervention
Cerivastatin (3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor)
C
Comparator
Untreated kl/kl mice and wild-type (+/+) mice
O
Outcome
Ischemia-induced angiogenesis and vasculogenesis (measured by laser Doppler blood-flow ratio, tissue capillary density, and rate of transplanted homologous bone marrow cells incorporated into capillaries)surrogate
In a mouse model of typical aging, impaired angiogenesis and vasculogenesis can be restored by statin therapy (cerivastatin).
Abstract
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. METHODS AND 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.