What is the role of pulmonary endothelium-derived vasodilators in the etiology of persistent pulmonary hypertension of the newborn (PPHN)?

Answer

Several events take place after birth as a fetus transitions from placental gas exchange to that taken care of by the lungs. At birth, the umbilical cord is clamped, which removes the low-resistance placenta circulation and increases the systemic circulation. In addition, pulmonary blood pressure begins to rapidly fall, leading to an increase in pulmonary blood flow.

The drop in pulmonary vascular resistance is due to several factors, including ventilation of the lungs causing an increase in oxygen tension and the release of several vasoactive factors by the pulmonary endothelium, including endothelin-1 (ET-1), nitric oxide (NO), and prostacyclin (PGI2). Endothelial nitric oxide synthase (eNOS) (or nitric oxide synthase type 3) is the most extensively studied enzyme in persistent pulmonary hypertension of the newborn (PPHN). When activated by shear stress or adenosine triphosphate (ATP), it converts L-arginine into NO and L-citrullin.

NO is a potent vasodilator and its production and release by the pulmonary endothelium rapidly increases after birth. The increase in oxygen tension is an important stimulator for this process. NO stimulates the soluble guanylate cyclase enzyme in the pulmonary vascular smooth muscle cells, leading to the conversion of guanosine triphosphate nucleotide into cyclic guanosine monophosphate (cGMP). The increase in intracellular cGMP leads to a decrease in calcium influx and relaxation of smooth muscle cells by stimulating protein kinase G.^{[9, 10]}cGMP is down-regulated by phosphodiesterase 5 activity. Phosphodiesterase 5, which is abundantly expressed in lung tissue, particularly during fetal life, is a key regulator of perinatal pulmonary circulation.^[11]

Experimental studies of chronic pulmonary hypertension in newborn animals have demonstrated impaired endothelial release of NO and increased production of vasoconstrictors (eg, endothelin-1).^[12]Endothelin-1, a 21–amino acid polypeptide elaborated by the endothelium, is a vasoconstrictor to the pulmonary arteries and enhances oxygen formation that depletes NO bioavailability and promotes the growth of the pulmonary artery muscular layer.

Vascular endothelial growth factor (VEGF) is another potent endothelial cell mitogen and regulator of angiogenesis. In vivo, inhibition of VEGF receptors in normal fetal sheep results in impaired vascular growth and leads to pulmonary hypertension.^[13]

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Persistent pulmonary hypertension of the newborn (PPHN). Meconium aspiration in a neonate. This radiograph was obtained shortly after birth and shows ill-defined, predominantly perihilar opacities in the lungs; these are more severe on the right than on the left. The lungs are hyperexpanded. The neonate's heart size is within normal limits.

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Author

Kate A Tauber, MD Assistant Professor of Pediatrics, Albany Medical College; Attending Neonatologist, Division of Neonatology, Bernard and Millie Duker Children’s Hospital at Albany Medical Center

Disclosure: Nothing to disclose.

Coauthor(s)

Gina M Geis, MD Attending Neonatologist, Associate Director, Neonatal-Perinatal Medicine Fellowship Program, Albany Medical Center; Assistant Professor, Department of Pediatrics, Albany Medical College

Gina M Geis, MD is a member of the following medical societies: American Academy of Pediatrics, American Society for Bioethics and Humanities, Capital District Pediatric Society

Disclosure: Nothing to disclose.

David A Clark, MD Professor and Martha Lepow Chairman of Pediatrics, Professor of Obstetrics and Gynecology, Albany Medical College; Director, Children's Hospital at Albany Medical Center

David A Clark, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Pediatrics, American College of Nutrition, American Forestry Association, American Pediatric Society, Capital District Pediatric Society, Christian Medical and Dental Associations, European Society for Paediatric Research, Eastern Society for Pediatric Research, Floyd W Denny Pediatric Alumni Society, Medical Society of the State of New York, New York Academy of Sciences, Society for Pediatric Research

Disclosure: Nothing to disclose.

Specialty Editor Board

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Arun K Pramanik, MD, MBBS Professor of Pediatrics, Louisiana State University Health Sciences Center

Arun K Pramanik, MD, MBBS is a member of the following medical societies: American Academy of Pediatrics, American Thoracic Society, National Perinatal Association, Southern Society for Pediatric Research

Disclosure: Nothing to disclose.

Chief Editor

Howard S Weber, MD, FSCAI Professor of Pediatrics, Section of Pediatric Cardiology, Pennsylvania State University College of Medicine; Director of Interventional Pediatric Cardiology, Penn State Hershey Children's Hospital

Howard S Weber, MD, FSCAI is a member of the following medical societies: Society for Cardiovascular Angiography and Interventions

Disclosure: Received income in an amount equal to or greater than $250 from: Abbott Medical .

Additional Contributors

Robert D Ross, MD Director of Pediatric Cardiology Fellowship Program, Department of Pediatrics, Division of Pediatric Cardiology, Children's Hospital of Michigan; Professor of Pediatrics, Wayne State University School of Medicine

Robert D Ross, MD is a member of the following medical societies: American Academy of Pediatrics, American College of Cardiology, American Heart Association, Society of Pediatric Echocardiography

Disclosure: Nothing to disclose.

Salaam Sallaam, MD Department of Cardiology, Seattle Children's Tri-Cities Clinic

Salaam Sallaam, MD is a member of the following medical societies: American Academy of Pediatrics, American College of Cardiology, American Society of Echocardiography

Disclosure: Nothing to disclose.

Acknowledgements

Robin H Steinhorn, MD Raymond and Hazel Speck Berry Professor of Pediatrics, Division Head of Neonatology, Vice Chair of Pediatrics, Northwestern University, The Feinberg School of Medicine

Robin H Steinhorn, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Pediatrics, American Heart Association, American Pediatric Society, American Thoracic Society, and Society for Pediatric Research

Disclosure: Nothing to disclose.

What is the role of pulmonary endothelium-derived vasodilators in the etiology of persistent pulmonary hypertension of the newborn (PPHN)?

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