title: ATP-sensitive potassium channel activation induces angiogenesis in vitro and in vivo.
abstract: Intense research is conducted to identify new molecular mechanisms of angiogenesis. Previous studies have shown that the angiogenic effects of hydrogen sulfide (H2S) depend on the activation of ATP-sensitive potassium channels (KATP) and that C-type natriuretic peptide (CNP), which can act through KATP, promotes endothelial cell growth. We therefore investigated whether direct KATP activation induces angiogenic responses and whether it is required for the endothelial responses to CNP or vascular endothelial growth factor (VEGF). Chick chorioallantoic membrane (CAM) angiogenesis was similarly enhanced by the direct KATP channel activator 2-nicotinamidoethyl acetate (SG-209) and by CNP or VEGF. The KATP inhibitors glibenclamide and 5-hydroxydecanoate (5-HD) reduced basal and abolished CNP-induced CAM angiogenesis. In vitro, the direct KATP openers nicorandil and SG-209 and the polypeptides VEGF and CNP increased proliferation and migration in bEnd.3 mouse endothelial cells. In addition, VEGF and CNP induced cord-like formation on Matrigel by human umbilical vein endothelial cells (HUVECs). All these in vitro endothelial responses were effectively abrogated by glibenclamide or 5-HD. In HUVECs, a small-interfering RNA-mediated decrease in the expression of the inwardly rectifying potassium channel (Kir) 6.1 subunit impaired cell migration and network morphogenesis in response to either SG-209 or CNP. We conclude that 1) direct pharmacologic activation of KATP induces angiogenic effects in vitro and in vivo, 2) angiogenic responses to CNP and VEGF depend on KATP activation and require the expression of the Kir6.1 KATP subunit, and 3) KATP activation may underpin angiogenesis to a variety of vasoactive stimuli, including H2S, VEGF, and CNP.
authors.affiliation: Laboratory of Molecular Pharmacology, Department of Pharmacy, University of Patras, Rio-Patras, Greece (B.U., A.Py., V.K., S.T.); and Department of Pharmacy, National and Kapodistrian University of Athens, Athens, Greece (A.Pa.).
authors.forename: Bukar
authors.initials: B
authors.lastname: Umaru
authors.affiliation: Laboratory of Molecular Pharmacology, Department of Pharmacy, University of Patras, Rio-Patras, Greece (B.U., A.Py., V.K., S.T.); and Department of Pharmacy, National and Kapodistrian University of Athens, Athens, Greece (A.Pa.).
authors.forename: Anastasia
authors.initials: A
authors.lastname: Pyriochou
authors.affiliation: Laboratory of Molecular Pharmacology, Department of Pharmacy, University of Patras, Rio-Patras, Greece (B.U., A.Py., V.K., S.T.); and Department of Pharmacy, National and Kapodistrian University of Athens, Athens, Greece (A.Pa.).
authors.forename: Vasileios
authors.initials: V
authors.lastname: Kotsikoris
authors.affiliation: Laboratory of Molecular Pharmacology, Department of Pharmacy, University of Patras, Rio-Patras, Greece (B.U., A.Py., V.K., S.T.); and Department of Pharmacy, National and Kapodistrian University of Athens, Athens, Greece (A.Pa.).
authors.forename: Andreas
authors.initials: A
authors.lastname: Papapetropoulos
authors.affiliation: Laboratory of Molecular Pharmacology, Department of Pharmacy, University of Patras, Rio-Patras, Greece (B.U., A.Py., V.K., S.T.); and Department of Pharmacy, National and Kapodistrian University of Athens, Athens, Greece (A.Pa.) stto@upatras.gr.
authors.forename: Stavros
authors.initials: S
authors.lastname: Topouzis
mesh_terms: D000818:Animals; D002460:Cell Line; D002465:Cell Movement; D049109:Cell Proliferation; D002642:Chick Embryo; D049033:Chorioallantoic Membrane / Q000098:blood supply* / Q000378:metabolism; D003094:Collagen; D004338:Drug Combinations; D042783:Endothelial Cells / Q000166:cytology / Q000502:physiology; D004730:Endothelium, Vascular / Q000166:cytology / Q000502:physiology; D006801:Humans; D054086:KATP Channels / Q000235:genetics / Q000378:metabolism*; D007797:Laminin; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D020098:Natriuretic Peptide, C-Type / Q000378:metabolism / Q000494:pharmacology; D018919:Neovascularization, Physiologic; D009536:Niacinamide / Q000031:analogs & derivatives / Q000494:pharmacology; D011509:Proteoglycans; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics
chemical_list: D004338:Drug Combinations; D054086:KATP Channels; D007797:Laminin; D011509:Proteoglycans; D034741:RNA, Small Interfering; C092520:uK-ATP-1 potassium channel; C059485:matrigel; D020098:Natriuretic Peptide, C-Type; D009536:Niacinamide; C035663:SG 209; D003094:Collagen; D051057:Proto-Oncogene Proteins c-akt; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3