title: MicroRNA-150 Modulates Ischemia-Induced Neovascularization in Atherosclerotic Conditions.
abstract: Hypercholesterolemia is an atherosclerotic condition that is associated with impaired neovascularization in response to ischemia. This study sought to define the role of microRNAs in that pathophysiology.
  
  
  
  Next-generation sequencing and quantitative reverse transcription polymerase chain reaction analyses identified miR-150 as a proangiogenic microRNA, which expression is significantly reduced in the ischemic muscles of hypercholesterolemic apolipoprotein E-deficient (ApoE-/-) mice, and in human umbilical vein endothelial cells exposed to oxidized low-density lipoprotein. Forced expression of miR-150 using a miR mimic could rescue oxidized low-density lipoprotein-mediated impairment of endothelial cell migration and tubule formation in vitro. In a mouse model of hindlimb ischemia, intramuscular injection of miR-150 mimic restored blood flow recuperation, vascular densities in ischemic muscles, and functional mobility in ApoE-/-mice. Treatment of ApoE-/-mice with miR-150 also increased the number and the activities of proangiogenic cells. miR-150 targets SRC kinase signaling inhibitor 1, an important regulator of Src (proto-oncogene tyrosine-protein kinase Src) activity. Here we found that hypercholesterolemia and oxidized low-density lipoprotein exposure are associated with increased SRC kinase signaling inhibitor 1 expression and decreased Src activity. However, treatment with miR-150 mimic reduces SRC kinase signaling inhibitor 1 expression and restores Src and downstream endothelial nitric oxide synthase and Akt (protein kinase B) activities both in vitro and in vivo. We also demonstrate the interrelation between miR-150 and SRC kinase signaling inhibitor 1 and their importance for endothelial cell angiogenic activities.
  
  
  
  Hypercholesterolemia is associated with reduced expression of miR-150, impaired Src signaling, and inefficient neovascularization in response to ischemia. Forced expression of miR-150 using a miR mimic could constitute a novel therapeutic strategy to improve ischemia-induced neovascularization in atherosclerotic conditions.
authors.affiliation: From the Department of Cardiovascular Research, Centre Hospitalier de l'Université de Montréal, Montréal, Québec, Canada.
authors.forename: Michel
authors.initials: M
authors.lastname: Desjarlais
authors.affiliation: From the Department of Cardiovascular Research, Centre Hospitalier de l'Université de Montréal, Montréal, Québec, Canada.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Dussault
authors.affiliation: From the Department of Cardiovascular Research, Centre Hospitalier de l'Université de Montréal, Montréal, Québec, Canada.
authors.forename: Wahiba
authors.initials: W
authors.lastname: Dhahri
authors.affiliation: From the Department of Cardiovascular Research, Centre Hospitalier de l'Université de Montréal, Montréal, Québec, Canada.
authors.forename: Raphael
authors.initials: R
authors.lastname: Mathieu
authors.affiliation: From the Department of Cardiovascular Research, Centre Hospitalier de l'Université de Montréal, Montréal, Québec, Canada. alain.rivard@umontreal.ca.
authors.forename: Alain
authors.initials: A
authors.lastname: Rivard
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000378:metabolism; D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005260:Female; D005280:Fenoterol; D020022:Genetic Predisposition to Disease; D006614:Hindlimb; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D006937:Hypercholesterolemia / Q000235:genetics / Q000378:metabolism; D007511:Ischemia / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D008077:Lipoproteins, LDL / Q000494:pharmacology; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000098:blood supply*; D018919:Neovascularization, Physiologic; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D000090063:Proto-Oncogene Mas; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034622:RNA Interference; D015398:Signal Transduction; D014162:Transfection; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D001057:Apolipoproteins E; D005280:Fenoterol; D008077:Lipoproteins, LDL; D035683:MicroRNAs; D052250:Nitric Oxide Synthase Type III; D000090063:Proto-Oncogene Mas; D051057:Proto-Oncogene Proteins c-akt; D019061:src-Family Kinases; C000715470:MAS1 protein, human; C533097:MIR150, human; C529101:Mirn150 microRNA, mouse; C532615:SRCIN1 protein, human; C099252:oxidized low density lipoprotein; C496314:NOS3 protein, human; C496315:Nos3 protein, mouse
keywords: angiogenesis; apolipoprotein; hypercholesterolemia; microRNA; neovascularization