In the fetus, a blood vessel known as the ductus arteriosus (DA) is essential for fetal life. However, this blood vessel is detrimental for life outside the womb and it normally closes after birth. Failure of the DA to close after birth results in a congenital heart condition known as patent DA (PDA), a condition that is a major problem for premature babies. Although the soluble factor prostaglandin E (PGE) is required to keep the DA open during fetal life, mice lacking the PGE receptor EP4 develop fatal PDA. A study appearing in the November issue of the Journal of Clinical Investigation now sheds light on this paradox by showing that EP4 is required for one of the processes that must occur for the DA to close.
Susumu Minamisawa and colleagues from Yokohama University, Japan, used several different approaches to show that in mice, EP4 signals are required for the in utero formation of a plug (known as the intimal cushion) that begins the process of closing the DA. Current treatment for PDA, the administration of drugs that inhibit the production of PGE (COX inhibitors), are less effective at inducing closure of the DA in severely premature babies than in near-term babies. This study, suggests that this decrease in effectiveness is likely to be due to the lack of formation of the intimal cushion and provides a rationale for developing strategies to stimulate intimal cushion formation to treat babies with PDA.
In an accompanying commentary, Kathryn Ivey and Deepak Srivastava from the University of California San Francisco discuss the clinical implications of this study and describe how it might help explain why the use of COX inhibitors by women who are pregnant increases the risk of PDA.
TITLE: Chronic activation of the prostaglandin receptor EP4 promotes hyaluronan-mediated neointimal formation in the ductus arteriosus
AUTHOR CONTACT:
Susumu Minamisawa
Yokohama City University, Yokohama, Japan.
ACCOMPANYING COMMENTARY
TITLE: The paradoxical patent ductus arteriosus
AUTHOR CONTACT:
Deepak Srivastava
University of California San Francisco, San Francisco, California, USA.
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Contact: Karen Honey
Journal of Clinical Investigation