Developmental Changes in Endothelial Vasoactive and Angiogenic Growth Factors in the Human Perinatal Lung

Abstract

Little is known of the mechanisms underlying the marked fall in pulmonary vascular resistance that occurs at birth, but changes in the expression of endothelial vasoactive and angiogenic factors during lung development might play a key role. Nitric oxide, endothelin-1, and vascular endothelial growth factor have critical effects on vascular tone and cell growth. Here, we investigated the protein expression of endothelial nitric oxide synthase, endothelin-1 and its receptors, and vascular endothelial growth factor in pulmonary necropsy samples from 14 fetuses of different gestational ages and from 5 infants. Expression of endothelin-1 and its receptor endothelin-A was strong and stable. In contrast, expression of the endothelin-B receptor was weak in early gestation, then increased markedly in mid-gestation and remained high thereafter. The expression of endothelial nitric oxide synthase and vascular endothelial growth factor fell markedly after mid-gestation and remained low thereafter. These data point to a discrepancy between maturational and functional changes in human pulmonary vascular structures. The weak perinatal expression of endothelial nitric oxide could suggest that other potent vasodilatory mediators are responsible for the marked vasodilation observed at birth. During gestation, the placenta ensures the totality of maternofetal gas exchange. Fetal lung development is associated with high PVR, with Ͻ10% of ventricular output entering the lungs. The mechanisms underlying these high PVR in fetal lung are not entirely clear and might involve lack of ventilation, low oxygen pressure, and, possibly, regulated expression of endothelial vasoactive and angiogenic factors with a preponderance of vasoconstrictive ones (1-3). The perinatal transition of gas exchanges from the placenta to the lungs at birth requires a marked and sharp decrease in PVR, allowing the pulmonary blood flow to increase 8-to 10-fold during the first hours of life. The mechanisms underlying this phenomenon have not been elucidated and appear to involve rhythmic distension of the lung, increased oxygenation, shear stress, and changes in vasoactive factor expression (3). In experimental animals, the basal pulmonary vessel tone appears to be tightly regulated by a balance between endothelium-derived mediators, some of which display major vasodilating effects, such as NO, EDHF, and prostacyclin, and some potent vasoconstrictive effects, such as and ET-1 and leukotrienes (4 -10). NO, for instance, produced from L-arginine by the action of a constitutive eNOS, is clearly involved in the postnatal fall in PVR in rats, lambs, and piglets (1,11,12). The effects of ET-1, mediated through two different sets of receptors, ET-A and ET-B, are more ambiguous (13). ET-A, mostly present on vascular smooth muscle cells, mediates vasoconstriction. ET-B, on the other hand, might participate both in the release of vasodilatory mediators such as NO when located on endothelial cells and in vasoconstriction through its location on vascular smooth muscle cells...

Airway Concentrations of Angiopoietin-1 and Endostatin in Ventilated Extremely Premature Infants Are Decreased After Funisitis and Unbalanced With Bronchopulmonary Dysplasia/Death

“…Increasing pulmonary expression of endothelial nitric oxide synthase, endothelin-1, and VEGF over gestation with a peak at the gestational age of the infants in our cohort-corresponding to the transition from the saccular to the alveolar phase of lung development-underlines the importance of angiogenesis for the process of alveolarization in human lungs (35). However, results of studies focusing on the association between postnatal concentrations of these factors in airways of ventilated preterm infants and evolving pulmonary disease have been inconsistent (36 -39).…”

Postnatal changes in pulmonary vein responses to endothelin-1 in the normal and chronically hypoxic lung

“…These changes are similar to those found in the pulmonary arteries of rabbits, where contractile response to ET-1 decreased and response to the ET-B agonist sarafotoxin S6c increased between birth and 7 days of age (7). In the human lung, expression of the ET-B receptor was lower in early gestation than soon after birth (20). Norepinephrine-induced contractile responses were also significantly higher in the fetal compared with 14-day-old and adult porcine pulmonary veins and arteries (26).…”

Heat shock protein 90-eNOS interactions mature with postnatal age in the pulmonary circulation of the piglet

“…Maturational changes in the regulation of pulmonary vascular tone by NO have been described in a number of species, including rat (10,26,36,49), pig (24), lamb (23,38), baboon (41), and human (30,31). Prior publications comparing fetal and postnatal expression of eNOS have demonstrated an increase in NOS expression during gestation that is maximal shortly before or at the time of birth (26, 36) with a subsequent decline postnatally to the low levels observed in adults (36,47,49).…”