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Am J Physiol Regul Integr Comp Physiol 282: R199-R206, 2002; doi:10.1152/ajpregu.00298.2001
0363-6119/02 $5.00
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Vol. 282, Issue 1, R199-R206, January 2002

VEGF regulates remodeling during permanent anatomic closure of the ductus arteriosus

Ronald I. Clyman1,2, Steven R. Seidner3, Hiroki Kajino1, Christine Roman1, Cameron J. Koch4, Napoleone Ferrara5, Nahid Waleh6, Françoise Mauray1, Yao Qi Chen1, Elizabeth A. Perkett7, and Timothy Quinn2

1 Cardiovascular Research Institute and 2 Department of Pediatrics, University of California, San Francisco, California 94143; 3 Department of Pediatrics, University of Texas Health Science Center and the Southwest Foundation for Biomedical Research, San Antonio, Texas 78284; 4 Department of Radiation Oncology, University of Pennsylvania, Philadelphia, Pennsylvania 19104; 5 Genentech, South San Francisco, California 94080; 6 SRI International, Menlo Park, California 78284; and 7 Department of Pediatrics, University of New Mexico, Albuquerque, New Mexico 87131

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.

nitric oxide; neointima; hypoxia; vasa vasorum


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