In utero remodeling of the fetal lamb ductus arteriosus: the role of antenatal indomethacin and avascular zone thickness on vasa vasorum proliferation, neointima formation, and cell death.
BACKGROUND
The ductus arteriosus (DA) of newborn infants exposed in utero to indomethacin is resistant to postnatal indomethacin; we hypothesized that this is due to ductus constriction in utero, with subsequent remodeling of the vessel.


RESULTS
Infusion of fetal lambs with indomethacin for 48 hours constricted the DA and increased the thickness of the avascular zone of the DA, which in turn induced the expression of vascular endothelial growth factor, endothelial nitric oxide synthase (due to ingrowth of vasa vasorum), neointima formation, and loss of smooth muscle cells; moderate degrees of DA constriction in utero increased NO production, which inhibited DA contractility. Marked degrees of DA constriction decreased tissue distensibility and contractile capacity.


CONCLUSIONS
DA patency is no longer controlled primarily by prostaglandins once it has been exposed to indomethacin in utero.
Clyman
R I
RI
Cardiovascular Research Institute, Department of Pediatrics, University of California, San Francisco, SanFrancisco, CA 94143-0544, USA. ric@itsa.ucsf.edu
Chen
Y Q
YQ
Chemtob
S
S
Mauray
F
F
Kohl
T
T
Varma
D R
DR
Roman
C
C
D015121:6-Ketoprostaglandin F1 alpha / Q000096:biosynthesis; D000818:Animals; D015153:Blotting, Western; D016923:Cell Death / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D003326:Coronary Circulation / Q000187:drug effects; D015232:Dinoprostone / Q000096:biosynthesis / Q000494:pharmacology; D004373:Ductus Arteriosus / Q000002:abnormalities* / Q000187:drug effects* / Q000196:embryology / Q000378:metabolism; D004374:Ductus Arteriosus, Patent / Q000139:chemically induced / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D016228:Endothelial Growth Factors / Q000096:biosynthesis; D005333:Fetus / Q000002:abnormalities* / Q000098:blood supply / Q000187:drug effects / Q000201:enzymology; D066298:In Vitro Techniques; D007213:Indomethacin / Q000494:pharmacology*; D008222:Lymphokines / Q000096:biosynthesis; D008954:Models, Biological; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000473:pathology; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III; D009599:Nitroprusside / Q000494:pharmacology; D011312:Pressure; D012756:Sheep / Q000002:abnormalities / Q000196:embryology*; D017539:Tunica Intima / Q000187:drug effects / Q000473:pathology; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D016228:Endothelial Growth Factors; D008222:Lymphokines; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D009599:Nitroprusside; D009569:Nitric Oxide; D015121:6-Ketoprostaglandin F1 alpha; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; D015232:Dinoprostone; D007213:Indomethacin