VEGF regulates remodeling during permanent anatomic closure of the ductus arteriosus.
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.
Clyman
Ronald I
RI
Cardiovascular Research Institute, University of California, San Francisco, California 94143-0544, USA.
Seidner
Steven R
SR
Kajino
Hiroki
H
Roman
Christine
C
Koch
Cameron J
CJ
Ferrara
Napoleone
N
Waleh
Nahid
N
Mauray
Françoise
F
Chen
Yao Qi
YQ
Perkett
Elizabeth A
EA
Quinn
Timothy
T
D000818:Animals; D000831:Animals, Newborn; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D004373:Ductus Arteriosus / Q000502:physiology*; D016228:Endothelial Growth Factors / Q000276:immunology / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism; D015870:Gene Expression / Q000502:physiology; D005865:Gestational Age; D000860:Hypoxia / Q000503:physiopathology; D008222:Lymphokines / Q000276:immunology / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D010215:Papio; D012333:RNA, Messenger / Q000032:analysis; D012756:Sheep; D017539:Tunica Intima / Q000166:cytology / Q000378:metabolism; D014651:Vasa Vasorum / Q000502:physiology; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D000911:Antibodies, Monoclonal; D016228:Endothelial Growth Factors; D008222:Lymphokines; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D009569:Nitric Oxide