VEGF regulates remodeling during permanent anatomic closure of the ductus arteriosus

Ronald I. Clyman, Steven R. Seidner, Hiroki Kajino, Christine Roman, Cameron J. Koch, Napoleone Ferrara, Nahid Waleh, Françoise Mauray, Yao Qi Chen, Elizabeth A. Perkett, Timothy Quinn

Research output: Contribution to journalArticlepeer-review

44 Scopus citations

Abstract

Anatomic remodeling and permanent closure of the newborn ductus arteriosus appears to require the development of intense hypoxia within the constricted vessel wall. Hypoxic ductus smooth muscle cells express vascular endothelial cell growth factor (VEGF). We studied premature baboons and sheep to determine the effects of VEGF inhibition (in baboons) and VEGF stimulation (in sheep) on ductus remodeling in vivo. For study of VEGF inhibition, 13 premature newborn baboons (68% gestation) were treated with inhibitors of both prostaglandin and nitric oxide production to constrict the ductus and induce ductus wall hypoxia. Six received a neutralizing monoclonal antibody against VEGF (A.4.6.1, mAbVEGF), while seven did not. Both groups developed the same degree of ductus constriction, tissue hypoxia, and VEGF expression. The mAbVEGF treatment produced a significant (P < 0.05) reduction in ductus vasa vasorum ingrowth and neointima formation (due to both a decrease in luminal endothelial cell proliferation and a decrease in smooth muscle cell migration into the neointima). For study of VEGF stimulation, nine sheep fetuses (70% gestation) had their ductus wall injected with either VEGF (n = 6) or vehicle (n = 4) in vivo. VEGF administration produced a significant (P < 0.05) increase in vasa vasorum ingrowth and neointima formation. We conclude that VEGF plays an important role in the formation of neointimal mounds and vasa vasorum ingrowth during permanent ductus closure.

Original languageEnglish (US)
Pages (from-to)R199-R206
JournalAmerican Journal of Physiology - Regulatory Integrative and Comparative Physiology
Volume282
Issue number1 51-1
DOIs
StatePublished - 2002

Keywords

  • Hypoxia
  • Neointima
  • Nitric oxide
  • Vasa vasorum

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)

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