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

Updated: Sep 03, 2019
  • Author: Kate A Tauber, MD; Chief Editor: Howard S Weber, MD, FSCAI  more...
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Answer

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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