title: Caloric restriction stimulates revascularization in response to ischemia via adiponectin-mediated activation of endothelial nitric-oxide synthase.
abstract: Caloric restriction (CR) can extend longevity and modulate the features of obesity-related metabolic and vascular diseases. However, the functional roles of CR in regulation of revascularization in response to ischemia have not been examined. Here we investigated whether CR modulates vascular response by employing a murine hindlimb ischemia model. Wild-type (WT) mice were randomly divided into two groups that were fed either ad libitum (AL) or CR (65% of the diet consumption of AL). Four weeks later, mice were subjected to unilateral hindlimb ischemic surgery. Body weight of WT mice fed CR (CR-WT) was decreased by 26% compared with WT mice fed AL (AL-WT). Revascularization of ischemic hindlimb relative to the contralateral limb was accelerated in CR-WT compared with AL-WT as evaluated by laser Doppler blood flow and capillary density analyses. CR-WT mice had significantly higher plasma levels of the fat-derived hormone adiponectin compared with AL-WT mice. In contrast to WT mice, CR did not affect the revascularization of ischemic limbs of adiponectin-deficient (APN-KO) mice. CR stimulated the phosphorylation of endothelial nitric-oxide synthase (eNOS) in the ischemic limbs of WT mice. CR increased plasma adiponectin levels in eNOS-KO mice but did not stimulate limb perfusion in this strain. CR-WT mice showed enhanced phosphorylation of AMP-activated protein kinase (AMPK) in ischemic muscle, and administration of AMPK inhibitor compound C abolished CR-induced increase in limb perfusion and eNOS phosphorylation in WT mice. Our observations indicate that CR can promote revascularization in response to tissue ischemia via an AMPK-eNOS-dependent mechanism that is mediated by adiponectin.
authors.affiliation: Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan.
authors.forename: Megumi
authors.initials: M
authors.lastname: Kondo
authors.forename: Rei
authors.initials: R
authors.lastname: Shibata
authors.forename: Rie
authors.initials: R
authors.lastname: Miura
authors.forename: Masayuki
authors.initials: M
authors.lastname: Shimano
authors.forename: Kazuhisa
authors.initials: K
authors.lastname: Kondo
authors.forename: Ping
authors.initials: P
authors.lastname: Li
authors.forename: Taiki
authors.initials: T
authors.lastname: Ohashi
authors.forename: Shinji
authors.initials: S
authors.lastname: Kihara
authors.forename: Norikazu
authors.initials: N
authors.lastname: Maeda
authors.forename: Kenneth
authors.initials: K
authors.lastname: Walsh
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Ouchi
authors.forename: Toyoaki
authors.initials: T
authors.lastname: Murohara
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D052242:Adiponectin / Q000097:blood*; D000818:Animals; D031204:Caloric Restriction; D006614:Hindlimb / Q000098:blood supply / Q000378:metabolism; D007511:Ischemia / Q000097:blood*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000098:blood supply / Q000378:metabolism*; D018919:Neovascularization, Physiologic; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D010766:Phosphorylation; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology
chemical_list: D052242:Adiponectin; D011720:Pyrazoles; D011743:Pyrimidines; C516138:dorsomorphin; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D055372:AMP-Activated Protein Kinases