Deficiency in endothelial nitric oxide synthase impairs myocardial angiogenesis

Am J Physiol Heart Circ Physiol. 2002 Dec;283(6):H2371-8. doi: 10.1152/ajpheart.00383.2002. Epub 2002 Aug 22.


We recently demonstrated that mice deficient in endothelial nitric oxide (NO) synthase (eNOS) have congenital septal defects and postnatal heart failure. However, the mechanisms by which eNOS affects heart development are not clear. We hypothesized that deficiency in eNOS impairs myocardial angiogenesis. Myocardial capillary densities were measured morphometrically in neonatal mouse hearts. In vitro tube formation on Matrigel was investigated in cardiac endothelial cells. In vivo myocardial angiogenesis was performed by implanting Matrigel in the left ventricular myocardium. Myocardial capillary densities and VEGF mRNA expression were decreased in neonatal eNOS(-/-) compared with neonatal wild-type mice (P < 0.01). Furthermore, in vitro tube formation from cardiac endothelial cells and in vivo myocardial angiogenesis were attenuated in eNOS(-/-) compared with wild-type mice (P < 0.01). In vitro tube formation was inhibited by N(G)-nitro-l-arginine methyl ester in wild-type mice and restored by a NO donor, diethylenetriamine-NO, in eNOS(-/-) mice (P < 0.05). In conclusion, deficiency in eNOS decreases VEGF expression and impairs myocardial angiogenesis and capillary development. Decreased myocardial angiogenesis may contribute to cardiac abnormalities during heart development in eNOS(-/-) mice.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Newborn
  • Capillaries / enzymology
  • Capillaries / pathology
  • Cell Count
  • Cell Transplantation / methods
  • Cells, Cultured
  • Collagen / administration & dosage
  • Coronary Circulation / genetics
  • Coronary Circulation / physiology*
  • Drug Combinations
  • Endothelium, Vascular / cytology
  • Endothelium, Vascular / drug effects
  • Endothelium, Vascular / transplantation
  • Enzyme Inhibitors / pharmacology
  • Heart Defects, Congenital / genetics
  • Heart Defects, Congenital / pathology*
  • Heart Ventricles / cytology
  • Heart Ventricles / surgery
  • Laminin / administration & dosage
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Myocardium / pathology*
  • Neovascularization, Physiologic / drug effects
  • Neovascularization, Physiologic / genetics
  • Neovascularization, Physiologic / physiology*
  • Nitric Oxide Donors / pharmacology
  • Nitric Oxide Synthase / deficiency*
  • Nitric Oxide Synthase / genetics
  • Nitric Oxide Synthase Type II
  • Nitric Oxide Synthase Type III
  • Proteoglycans / administration & dosage
  • Ventricular Function


  • Drug Combinations
  • Enzyme Inhibitors
  • Laminin
  • Nitric Oxide Donors
  • Proteoglycans
  • matrigel
  • Collagen
  • Nitric Oxide Synthase
  • Nitric Oxide Synthase Type II
  • Nitric Oxide Synthase Type III
  • Nos3 protein, mouse