title: High concentration of C-type natriuretic peptide promotes VEGF-dependent vasculogenesis in the remodeled region of infarcted swine heart with preserved left ventricular ejection fraction.
abstract: BACKGROUND
  Vasculogenesis is a hallmark of myocardial restoration. Post-ischemic late remodeling is associated with pathology and function worsening. At the same time, neo-vasculogenesis helps function improving and requires the release of vascular endothelial growth factor type A (VEGF-A). The vasculogenic role of C-type natriuretic peptide (CNP), a cardiac paracrine hormone, is unknown in infarcted hearts with preserved left ventricular (LV) ejection fraction (EF). We explored whether myocardial VEGF-dependent vasculogenesis is affected by CNP.
  
  
  RESULTS
  To this end, infarcted swine hearts were investigated by magnetic resonance imaging (MRI), histological and molecular assays. At the fourth week, MRI showed that transmural myocardial infarction (MI) affected approximately 13% of the LV wall mass without impairing global function (LVEF>50%, n=9). Increased fibrosis, metalloproteases and capillary density were localized to the infarct border zone (BZ), and were associated with increased expression of CNP (p=0.03 vs. remote zone (RZ)), VEGF-A (p<0.001 vs. RZ), BNP, a marker of myocardial dysfunction (p<0.01 vs. RZ) and the endothelial marker, factor VIII-related antigen (p<0.01 vs. RZ). In vitro, CNP 1000 nM promoted VEGF-dependent vasculogenesis without affecting the cell growth and survival, although CNP 100 nM or a high concentration of VEGF-A halted vascular growth.
  
  
  CONCLUSIONS
  CNP expression is locally increased in infarct remodeled myocardium in the presence of dense capillary network. The vasculogenic response requires the co-exposure to high concentration of CNP and VEGF-A. Our data will be helpful to develop combined myocardial delivery of CNP and VEGF-A genes in order to reverse the remodeling process.
authors.affiliation: CNR Institute of Clinical Physiology, Laboratory of Cardiovascular Biochemistry, Pisa, Italy. Electronic address: delry@ifc.cnr.it.
authors.forename: S
authors.initials: S
authors.lastname: Del Ry
authors.forename: M
authors.initials: M
authors.lastname: Cabiati
authors.forename: A
authors.initials: A
authors.lastname: Martino
authors.forename: C
authors.initials: C
authors.lastname: Cavallini
authors.forename: C
authors.initials: C
authors.lastname: Caselli
authors.forename: G D
authors.initials: GD
authors.lastname: Aquaro
authors.forename: B
authors.initials: B
authors.lastname: Battolla
authors.forename: T
authors.initials: T
authors.lastname: Prescimone
authors.forename: D
authors.initials: D
authors.lastname: Giannessi
authors.forename: L
authors.initials: L
authors.lastname: Mattii
authors.forename: V
authors.initials: V
authors.lastname: Lionetti
mesh_terms: D000818:Animals; D008297:Male; D009203:Myocardial Infarction / Q000503:physiopathology*; D020098:Natriuretic Peptide, C-Type / Q000502:physiology*; D018919:Neovascularization, Physiologic / Q000502:physiology*; D013552:Swine; D042461:Vascular Endothelial Growth Factor A / Q000502:physiology*; D016277:Ventricular Function, Left; D020257:Ventricular Remodeling
chemical_list: D042461:Vascular Endothelial Growth Factor A; D020098:Natriuretic Peptide, C-Type
keywords: C-type natriuretic peptide; Ischemic remodeling; Myocardial infarction; Paracrinicity; VEGF; Vasculogenesis