title: Pitavastatin-induced angiogenesis and arteriogenesis is mediated by Notch1 in a murine hindlimb ischemia model without induction of VEGF.
abstract: Notch signaling is reported to regulate angiogenesis, interacting with vascular endothelial growth factor (VEGF) signaling. HMG CoA reductase inhibitors (statins) also alter Notch signaling in vascular cells, but the mechanism and involvement of Notch and VEGF signaling in statin-mediated angiogenesis remain unclear. Here, we examined how statins activate the endothelial Notch1, and promote angiogenesis and arteriogenesis. We examined blood flow recovery after hindlimb ischemia in wild-type (WT) and Notch1 mutant mice treated with or without pitavastatin (3 mg/kg/day, p.o.). Although VEGF induction was not altered in ischemic limbs, pitavastatin promoted blood flow recovery in ischemic limbs in control mice but not in Notch1 mutant mice. Furthermore, pitavastatin induced endothelial ephrinB2 downstream of Notch1 and increased the density of both capillaries and arterioles in the ischemic limbs of WT but not of Notch1 mutant mice. Pitavastatin (100 nmol/l) rapidly activated γ-secretase and Notch1 in human umbilical vein endothelial cells without VEGF induction, which was suppressed by pharmacological inhibition and knockdown of Akt. Pitavastatin also augmented endothelial proliferation and tube formation on Matrigel, which were suppressed by either γ-secretase inhibition or knockdown of Notch1. Pitavastatin-induced microvascular sprouting was also impaired in Notch1 mutant aortic explants. Taken together, pitavastatin activates Notch1 through Akt-dependent stimulation of γ-secretase in endothelial cells, and thereby increases vasculogenesis without VEGF induction.
authors.affiliation: Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Kikuchi
authors.forename: Kyosuke
authors.initials: K
authors.lastname: Takeshita
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Uchida
authors.forename: Megumi
authors.initials: M
authors.lastname: Kondo
authors.forename: Xian Wu
authors.initials: XW
authors.lastname: Cheng
authors.forename: Takayuki
authors.initials: T
authors.lastname: Nakayama
authors.forename: Koji
authors.initials: K
authors.lastname: Yamamoto
authors.forename: Tadashi
authors.initials: T
authors.lastname: Matsushita
authors.forename: James K
authors.initials: JK
authors.lastname: Liao
authors.forename: Toyoaki
authors.initials: T
authors.lastname: Murohara
mesh_terms: D000818:Animals; D001158:Arteries / Q000187:drug effects* / Q000254:growth & development; D001775:Blood Circulation / Q000187:drug effects / Q000502:physiology; D015153:Blotting, Western; D002460:Cell Line; D004195:Disease Models, Animal; D006614:Hindlimb / Q000098:blood supply*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D007150:Immunohistochemistry; D007511:Ischemia / Q000503:physiopathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009389:Neovascularization, Pathologic; D011804:Quinolines / Q000494:pharmacology*; D051881:Receptor, Notch1 / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis*
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011804:Quinolines; D051881:Receptor, Notch1; D042461:Vascular Endothelial Growth Factor A; C108475:pitavastatin