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(Circulation. 2001;103:1806.)
© 2001 American Heart Association, Inc.

Basic Science Reports

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

Ronald I. Clyman, MD; Yao Qi Chen, MS; Sylvain Chemtob, MD, PhD; Françoise Mauray, BS; Thomas Kohl, MD; Daya R. Varma, MD, PhD; Christine Roman, BS

From the Cardiovascular Research Institute (R.I.C., Y.Q.C., F.M., T.K., C.R.) and Department of Pediatrics (R.I.C., T.K.), University of California, San Francisco; and the Research Center, Hôpital Sainte-Justine (S.C.), and Department of Pharmacology, McGill University (S.C., D.R.V.), Montreal, Québec, Canada.

Correspondence to Ronald I. Clyman, MD, Box 0544, HSE 1492, University of California, San Francisco, San Francisco, CA 94143-0544. E-mail ric{at}itsa.ucsf.edu

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.

Methods and 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.

Key Words: nitric oxide synthase • prostaglandins • endothelium-derived factors • nitric oxide • pregnancy

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