title: Arteriogenic therapy by intramyocardial sustained delivery of a novel growth factor combination prevents chronic heart failure.
abstract: BACKGROUND
  Therapeutic angiogenesis is a promising approach for the treatment of cardiovascular diseases, including myocardial infarction and chronic heart failure. We aimed to improve proangiogenic therapies by identifying novel arteriogenic growth factor combinations, developing injectable delivery systems for spatiotemporally controlled growth factor release, and evaluating functional consequences of targeted intramyocardial growth factor delivery in chronic heart failure.
  
  
  RESULTS
  First, we observed that fibroblast growth factor and hepatocyte growth factor synergistically stimulate vascular cell migration and proliferation in vitro. Using 2 in vivo angiogenesis assays (n=5 mice per group), we found that the growth factor combination results in a more potent and durable angiogenic response than either growth factor used alone. Furthermore, we determined that the molecular mechanisms involve potentiation of Akt and mitogen-activated protein kinase signal transduction pathways, as well as upregulation of angiogenic growth factor receptors. Next, we developed crosslinked albumin-alginate microcapsules that sequentially release fibroblast growth factor-2 and hepatocyte growth factor. Finally, in a rat model of chronic heart failure induced by coronary ligation (n=14 to 15 rats per group), we found that intramyocardial slow release of fibroblast growth factor-2 with hepatocyte growth factor potently stimulates angiogenesis and arteriogenesis and prevents cardiac hypertrophy and fibrosis, as determined by immunohistochemistry, leading to improved cardiac perfusion after 3 months, as shown by magnetic resonance imaging. These multiple beneficial effects resulted in reduced adverse cardiac remodeling and improved left ventricular function, as revealed by echocardiography.
  
  
  CONCLUSIONS
  Our data showing the selective advantage of using fibroblast growth factor-2 together with hepatocyte growth factor suggest that this growth factor combination may constitute an efficient novel treatment for chronic heart failure.
authors.affiliation: Inserm U644, Institute for Biomedical Research, Rouen University, 22 Blvd Gambetta, 76183 Rouen, France.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Banquet
authors.forename: Elodie
authors.initials: E
authors.lastname: Gomez
authors.forename: Lionel
authors.initials: L
authors.lastname: Nicol
authors.forename: Florence
authors.initials: F
authors.lastname: Edwards-Lévy
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Henry
authors.forename: Renhai
authors.initials: R
authors.lastname: Cao
authors.forename: Damien
authors.initials: D
authors.lastname: Schapman
authors.forename: Brigitte
authors.initials: B
authors.lastname: Dautreaux
authors.forename: Francoise
authors.initials: F
authors.lastname: Lallemand
authors.forename: Fabrice
authors.initials: F
authors.lastname: Bauer
authors.forename: Yihai
authors.initials: Y
authors.lastname: Cao
authors.forename: Christian
authors.initials: C
authors.lastname: Thuillez
authors.forename: Paul
authors.initials: P
authors.lastname: Mulder
authors.forename: Vincent
authors.initials: V
authors.lastname: Richard
authors.forename: Ebba
authors.initials: E
authors.lastname: Brakenhielm
mesh_terms: D043925:Angiogenesis Inducing Agents / Q000008:administration & dosage*; D000818:Animals; D002214:Capsules; D006332:Cardiomegaly / Q000188:drug therapy / Q000517:prevention & control; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002908:Chronic Disease; D003331:Coronary Vessels / Q000187:drug effects / Q000503:physiopathology; D004359:Drug Therapy, Combination; D016222:Fibroblast Growth Factor 2 / Q000008:administration & dosage*; D006333:Heart Failure / Q000517:prevention & control*; D017228:Hepatocyte Growth Factor / Q000008:administration & dosage*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009206:Myocardium; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D051058:Oncogene Protein v-akt / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar
chemical_list: D043925:Angiogenesis Inducing Agents; D002214:Capsules; D016222:Fibroblast Growth Factor 2; D017228:Hepatocyte Growth Factor; D051058:Oncogene Protein v-akt; D020928:Mitogen-Activated Protein Kinases