title: Vildagliptin stimulates endothelial cell network formation and ischemia-induced revascularization via an endothelial nitric-oxide synthase-dependent mechanism.
abstract: Dipeptidyl peptidase-4 inhibitors are known to lower glucose levels and are also beneficial in the management of cardiovascular disease. Here, we investigated whether a dipeptidyl peptidase-4 inhibitor, vildagliptin, modulates endothelial cell network formation and revascularization processes in vitro and in vivo. Treatment with vildagliptin enhanced blood flow recovery and capillary density in the ischemic limbs of wild-type mice, with accompanying increases in phosphorylation of Akt and endothelial nitric-oxide synthase (eNOS). In contrast to wild-type mice, treatment with vildagliptin did not improve blood flow in ischemic muscles of eNOS-deficient mice. Treatment with vildagliptin increased the levels of glucagon-like peptide-1 (GLP-1) and adiponectin, which have protective effects on the vasculature. Both vildagliptin and GLP-1 increased the differentiation of cultured human umbilical vein endothelial cells (HUVECs) into vascular-like structures, although vildagliptin was less effective than GLP-1. GLP-1 and vildagliptin also stimulated the phosphorylation of Akt and eNOS in HUVECs. Pretreatment with a PI3 kinase or NOS inhibitor blocked the stimulatory effects of both vildagliptin and GLP-1 on HUVEC differentiation. Furthermore, treatment with vildagliptin only partially increased the limb flow of ischemic muscle in adiponectin-deficient mice in vivo. GLP-1, but not vildagliptin, significantly increased adiponectin expression in differentiated 3T3-L1 adipocytes in vitro. These data indicate that vildagliptin promotes endothelial cell function via eNOS signaling, an effect that may be mediated by both GLP-1-dependent and GLP-1-independent mechanisms. The beneficial activity of GLP-1 for revascularization may also be partially mediated by its ability to increase adiponectin production.
authors.affiliation: Department of Cardiology, Nagoya University Graduate School of Medicine, 466-8550 Nagoya, Japan,; Department of Oral and Maxillofacial Prosthodontics, Kagoshima University Graduate school of Medical and Dental Science, 890-8544 Kagoshima, Japan.
authors.forename: Masakazu
authors.initials: M
authors.lastname: Ishii
authors.affiliation: Department of Cardiology, Nagoya University Graduate School of Medicine, 466-8550 Nagoya, Japan,. Electronic address: rshibata@med.nagoya-u.ac.jp.
authors.forename: Rei
authors.initials: R
authors.lastname: Shibata
authors.affiliation: Department of Cardiology, Nagoya University Graduate School of Medicine, 466-8550 Nagoya, Japan.
authors.forename: Kazuhisa
authors.initials: K
authors.lastname: Kondo
authors.affiliation: Department of Cardiology, Nagoya University Graduate School of Medicine, 466-8550 Nagoya, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Kambara
authors.affiliation: Department of Cardiology, Nagoya University Graduate School of Medicine, 466-8550 Nagoya, Japan.
authors.forename: Yuuki
authors.initials: Y
authors.lastname: Shimizu
authors.affiliation: Department of Otolaryngology, Aichi Medical University, 480-1195 Nagakute, Japan.
authors.forename: Tohru
authors.initials: T
authors.lastname: Tanigawa
authors.affiliation: Department of Cardiology, Nagoya University Graduate School of Medicine, 466-8550 Nagoya, Japan.
authors.forename: Yasuko K
authors.initials: YK
authors.lastname: Bando
authors.affiliation: Department of Oral and Maxillofacial Prosthodontics, Kagoshima University Graduate school of Medical and Dental Science, 890-8544 Kagoshima, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Nishimura
authors.affiliation: Department of Molecular Cardiology, Nagoya University Graduate School of Medicine, 466-8550 Nagoya, Japan, and.
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Ouchi
authors.affiliation: Department of Cardiology, Nagoya University Graduate School of Medicine, 466-8550 Nagoya, Japan,. Electronic address: murohara@med.nagoya-u.ac.jp.
authors.forename: Toyoaki
authors.initials: T
authors.lastname: Murohara
mesh_terms: D041721:3T3-L1 Cells; D000218:Adamantane / Q000031:analogs & derivatives* / Q000494:pharmacology; D017667:Adipocytes / Q000378:metabolism; D052242:Adiponectin / Q000378:metabolism; D000818:Animals; D002454:Cell Differentiation; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000494:pharmacology*; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism; D006614:Hindlimb / Q000098:blood supply / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism*; D007511:Ischemia / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000098:blood supply / Q000378:metabolism*; D018919:Neovascularization, Physiologic; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D009570:Nitriles / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011759:Pyrrolidines / Q000494:pharmacology*; D015398:Signal Transduction; D000077597:Vildagliptin
chemical_list: C499918:ADIPOQ protein, human; D052242:Adiponectin; C499919:Adipoq protein, mouse; D054873:Dipeptidyl-Peptidase IV Inhibitors; D009570:Nitriles; D011759:Pyrrolidines; D052216:Glucagon-Like Peptide 1; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D000077597:Vildagliptin; D000218:Adamantane
keywords: Adiponectin; Angiogenesis; Endothelial Cell; Nitric-oxide Synthase; Signaling
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