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: Masakazu Ishii, Rei Shibata, Kazuhisa Kondo, Takahiro Kambara, Yuuki Shimizu, Tohru Tanigawa, Yasuko K Bando, Masahiro Nishimura, Noriyuki Ouchi, Toyoaki Murohara
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 289 Issue 39 Pg. 27235-27245 (Sep 26 2014) ISSN: 1083-351X [Electronic] United States
• PMID: 25100725 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

Chemical References

• ADIPOQ protein, human
• Adiponectin
• Adipoq protein, mouse
• Dipeptidyl-Peptidase IV Inhibitors
• Nitriles
• Pyrrolidines
• Glucagon-Like Peptide 1
• NOS3 protein, human
• Nitric Oxide Synthase Type III
• Nos3 protein, mouse
• Phosphatidylinositol 3-Kinases
• Proto-Oncogene Proteins c-akt
• Vildagliptin
• Adamantane

Topics

• 3T3-L1 Cells
• Adamantane (analogs & derivatives, pharmacology)
• Adipocytes (metabolism)
• Adiponectin (metabolism)
• Animals
• Cell Differentiation
• Dipeptidyl-Peptidase IV Inhibitors (pharmacology)
• Glucagon-Like Peptide 1 (metabolism)
• Hindlimb (blood supply, metabolism)
• Human Umbilical Vein Endothelial Cells (metabolism)
• Ischemia (metabolism)
• Mice
• Mice, Knockout
• Muscle, Skeletal (blood supply, metabolism)
• Neovascularization, Physiologic
• Nitric Oxide Synthase Type III (metabolism)
• Nitriles (pharmacology)
• Phosphatidylinositol 3-Kinases (metabolism)
• Proto-Oncogene Proteins c-akt (metabolism)
• Pyrrolidines (pharmacology)
• Signal Transduction
• Vildagliptin