title: Vascular endothelial growth factor blockade prevents the beneficial effects of β-blocker therapy on cardiac function, angiogenesis, and remodeling in heart failure.
abstract: BACKGROUND
  Impaired angiogenesis in the post-myocardial infarction heart contributes to the progression to heart failure. The inhibition of vascular endothelial growth factor (VEGF) signaling has been shown to be crucial for the transition from compensatory hypertrophy to cardiac failure. Importantly, β-adrenergic receptor blocker therapy has been also shown to improve myocardial perfusion by enhancing neoangiogenesis in the failing heart.
  
  
  RESULTS
  Eight weeks from surgically induced myocardial infarction, heart failure rats were randomized to receive bisoprolol (B) or vehicle. At the end of a 10-week treatment period, echocardiography revealed reduced cardiac diameters and improved cardiac function in B-treated compared with vehicle-treated rats. Moreover, B treatment was associated with increased cardiac angiogenesis and in vivo coronary perfusion and reduced cardiac fibrosis. Importantly, 2 weeks after B treatment was started, increased cardiac VEGF expression and Akt and endothelial NO synthase activation were observed by comparing B-treated with drug-untreated failing hearts. To test whether the proangiogenic effects of B act via activation of VEGF pathway, rats were intravenously injected with adenoviral vector encoding a decoy VEGF receptor (Ad-Flk) or a control adenovirus (Ad-C), at the start of the treatment with B. After 10 weeks, histological analysis revealed reduced capillary and coronary perfusion in B-treated plus Ad-Flk rats compared with B-treated plus Ad-C rats. Moreover, VEGF inhibition counteracted the positive effects of B on cardiac function and remodeling.
  
  
  CONCLUSIONS
  β-Blockade promotes cardiac angiogenesis in heart failure via activation of VEGF signaling pathway. β-Blocker-induced enhancement of cardiac angiogenesis is essential for the favorable effects of this therapy on cardiac function and remodeling.
authors.affiliation: Division of Cardiology, "Salvatore Maugeri" Foundation-IRCCS-Institute of Telese Terme.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Rengo
authors.forename: Alessandro
authors.initials: A
authors.lastname: Cannavo
authors.forename: Daniela
authors.initials: D
authors.lastname: Liccardo
authors.forename: Carmela
authors.initials: C
authors.lastname: Zincarelli
authors.forename: Claudio
authors.initials: C
authors.lastname: de Lucia
authors.forename: Gennaro
authors.initials: G
authors.lastname: Pagano
authors.forename: Klara
authors.initials: K
authors.lastname: Komici
authors.forename: Valentina
authors.initials: V
authors.lastname: Parisi
authors.forename: Oriana
authors.initials: O
authors.lastname: Scala
authors.forename: Alessia
authors.initials: A
authors.lastname: Agresta
authors.forename: Antonio
authors.initials: A
authors.lastname: Rapacciuolo
authors.forename: Pasquale
authors.initials: P
authors.lastname: Perrone Filardi
authors.forename: Nicola
authors.initials: N
authors.lastname: Ferrara
authors.forename: Walter J
authors.initials: WJ
authors.lastname: Koch
authors.forename: Bruno
authors.initials: B
authors.lastname: Trimarco
authors.forename: Grazia Daniela
authors.initials: GD
authors.lastname: Femminella
authors.forename: Dario
authors.initials: D
authors.lastname: Leosco
mesh_terms: D058671:Adrenergic beta-1 Receptor Antagonists / Q000627:therapeutic use*; D000818:Animals; D017298:Bisoprolol / Q000627:therapeutic use*; D003326:Coronary Circulation / Q000187:drug effects*; D004195:Disease Models, Animal; D006333:Heart Failure / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008297:Male; D009206:Myocardium / Q000378:metabolism / Q000473:pathology*; D018919:Neovascularization, Physiologic / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors*; D020257:Ventricular Remodeling / Q000187:drug effects*
chemical_list: D058671:Adrenergic beta-1 Receptor Antagonists; D042461:Vascular Endothelial Growth Factor A; D017298:Bisoprolol
keywords: adrenergic β-1 receptor antagonists; angiogenesis; heart failure; vascular endothelial growth factor A