title: β2-Adrenergic receptor stimulation improves endothelial progenitor cell-mediated ischemic neoangiogenesis.
abstract: BACKGROUND
  Endothelial progenitor cells (EPCs) are present in the systemic circulation and home to sites of ischemic injury where they promote neoangiogenesis. β2-Adrenergic receptor (β2AR) plays a critical role in vascular tone regulation and neoangiogenesis.
  
  
  OBJECTIVE
  We aimed to evaluate the role of β2AR on EPCs' function.
  
  
  RESULTS
  We firstly performed in vitro analysis showing the expression of β2AR on EPCs. Stimulation of wild-type EPCs with β-agonist isoproterenol induced a significant increase of Flk-1 expression on EPCs as assessed by fluorescence-activated cell sorter. Moreover, β2AR stimulation induced a significant increase of cell proliferation, improved the EPCs migratory activity, and enhanced the EPCs' ability to promote endothelial cell network formation in vitro. Then, we performed in vivo studies in animals model of hindlimb ischemia. Consistent with our in vitro results, in vivo EPCs' treatment resulted in an improvement of impaired angiogenic phenotype in β2AR KO mice after induction of ischemia, whereas no significant amelioration was observed when β2AR knock out (KO) EPCs were injected. Indeed, wild-type-derived EPCs' injection resulted in a significantly higher blood flow restoration in ischemic hindlimb and higher capillaries density at histological analysis as compared with not treated or β2AR KO EPC-treated mice.
  
  
  CONCLUSIONS
  The present study provides the first evidence that EPCs express a functional β2AR. Moreover, β2AR stimulation results in EPCs proliferation, migration, and differentiation, enhancing their angiogenic ability, both in vitro and in vivo, leading to an improved response to ischemic injury in animal models of hindlimb ischemia.
authors: Department of Medicine and Surgery, University of Salerno, San Giovanni di Dio and Ruggi D'Aragona Academic Hospital, Cardiology Tower, Room S1, Largo Città d'Ippocrate, 84131 Salerno, Italy.
authors: Gennaro
authors: G
authors: Galasso
authors: Roberta
authors: R
authors: De Rosa
authors: Michele
authors: M
authors: Ciccarelli
authors: Daniela
authors: D
authors: Sorriento
authors: Carmine
authors: C
authors: Del Giudice
authors: Teresa
authors: T
authors: Strisciuglio
authors: Chiara
authors: C
authors: De Biase
authors: Rossella
authors: R
authors: Luciano
authors: Raffaele
authors: R
authors: Piccolo
authors: Adele
authors: A
authors: Pierri
authors: Giuseppe
authors: G
authors: Di Gioia
authors: Nella
authors: N
authors: Prevete
authors: Bruno
authors: B
authors: Trimarco
authors: Federico
authors: F
authors: Piscione
authors: Guido
authors: G
authors: Iaccarino
mesh_terms: D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D002908:Chronic Disease; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D006412:Hematopoietic Stem Cells / Q000502:physiology*; D006614:Hindlimb / Q000098:blood supply; D007511:Ischemia / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology*; D007545:Isoproterenol / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018919:Neovascularization, Physiologic / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D011921:Rats, Inbred WKY; D018343:Receptors, Adrenergic, beta-2 / Q000235:genetics / Q000378:metabolism*
chemical_list: D000318:Adrenergic beta-Agonists; D018343:Receptors, Adrenergic, beta-2; D007545:Isoproterenol