Control of the pulmonary circulation in the fetus and during the transitional period to air breathing

https://doi.org/10.1016/S0301-2115(98)00321-2Get rights and content

Abstract

During fetal life and the transition to extra-uterine air breathing, pulmonary vascular tone is regulated by a complex, interactive group of mechanisms. Arachidonic acid metabolites play an important role in this regulation. Although prostaglandins may not be central to regulation of the resting fetal pulmonary circulation, PGI2 acts to modulate tone and thereby maintain pulmonary vascular resistance relatively constant. PGI2 also may play an important role as one of the components involved in the major changes that occur with the onset of air breathing. Leukotrienes, also metabolites of arachidonic acid and potent smooth muscle constrictors, may play an active role in maintaining the normally high fetal pulmonary vascular resistance, because leukotriene receptor blockade or synthesis inhibition increases pulmonary blood flow about eight-fold; the presence of leukotrienes in fetal tracheal fluid further supports this. In addition to PGI2, vascular endothelial cells produce other vasoactive factors. These include potent vasodilators, such as endothelium-derived relaxing factor (EDRF). EDRF, known to be nitric oxide (NO) and often called endothelium-derived nitric oxide (EDNO), is produced by endothelial cells in response to varied stimuli, generally involving specific receptors and the activation of endothelial NO synthetase (eNOS); subsequent smooth muscle relaxation is produced by a NO/guanylyl cyclase/cGMP–mediated mechanism. NO clearly is involved in regulation of vascular tone in the fetal pulmonary circulation, although it plays a far more important role in the postnatal transition to air breathing. Superfused fetal sheep pulmonary arteries release NO when stimulated with bradykinin. In fetal lambs the vasodilating effects of bradykinin are attenuated by methylene blue and resting tone falls with Nω-nitro-l-arginine, an inhibitor of NO synthesis, suggesting that a NO/cGMP-dependent mechanism continuously modulates or offsets the increased tone of the resting fetal pulmonary circulation. Inhibition of NO synthesis blocks the pulmonary vasodilation with oxygenation of fetal lungs in utero. Shear stress-induced NO production as well as the relationship of oxygenation to NO production further support the important function of NO in the transition. Although endothelin-1 (ET-1) has potent vasoactivity as well as ontogenetic differences in effect on pulmonary vascular resistance, its exact physiological role has not been defined. Adrenomedullin and calcitonin gene-related peptide (CGRP), two additional vasoactive substances, have profound, and prolonged, vasodilating effects in the fetal pulmonary circulation. Their physiological roles have not yet been established.

Introduction

In the fetus, gas exchange occurs in the placenta. Pulmonary vascular resistance is high, and pulmonary blood flow low (about 35 ml/min/kg fetal body weight in term fetal lambs); thus, right ventricular output is directed to the placenta for gas exchange. At the time of birth and the onset of pulmonary ventilation, pulmonary vascular resistance falls dramatically, and pulmonary blood flow increases rapidly to 300–400 ml/min/kg body weight shortly after birth [1].

Many factors regulate pulmonary blood flow in these critical periods, including mechanical influences and the release of a variety of vasoactive substances. Mediators produced and released by the pulmonary vascular endothelium, either locally or into the circulation (paracrine or endocrine function), are central to many of these phenomena. Much of our knowledge of fetal blood flow and distribution is based on animal studies. Data on human fetuses and newborns are sparse because of the invasive techniques that would be necessary to obtain them. Although the applicability of these animal studies to humans could be questioned, historically, overlapping data obtained in animal studies and humans on the pulmonary circulation have had excellent correlation.

In the fetus, normal gas exchange is placental in origin and pulmonary blood flow is low, merely supplying nutritional requirements for lung growth and some metabolic functions. In near-term lambs, pulmonary blood flow is about 100 ml/min/100 g lung weight, 8–10% of fetal cardiac output [2]. In human fetuses near term, this value is about 25% of total cardiac output [3]. Fetal pulmonary blood flow is low despite the dominance of the right ventricle, which ejects about two-thirds of total cardiac output. Most of the right ventricular output is diverted away from the lungs through the widely patent ductus arteriosus to the descending thoracic aorta, then reaches the placenta through the umbilical circulation for oxygenation. In young fetal lambs (about 0.5 of gestation), pulmonary blood flow is approximately 3–4% of the total fetal cardiac output. This value increases to about 6% at about 0.8 gestation, corresponding temporally with the onset of the release of surface active material into lung fluid. This is followed by another progressive, slow rise in pulmonary blood flow, reaching about 8–10% near term [2]. Pulmonary vascular resistance early in gestation is extremely high relative to that in the infant and adult, probably due to the reduced number of small arteries. During the last half of gestation, new arteries develop, cross-sectional area increases, and pulmonary vascular resistance falls progressively; however, baseline pulmonary vascular resistance is still much higher than after birth [1], [4].

In unventilated fetal lungs, fluid filling the alveolar space compresses the small pulmonary arteries, thereby increasing pulmonary vascular resistance. In addition, a high pulmonary vascular resistance is associated with the normally low O2 tension in pulmonary and systemic arterial blood (pulmonary arterial blood pO2 is 17–20 mmHg [~2.6 kPa]). Conversely, fetal pulmonary vascular resistance is decreased by increasing pO2 [5]. The exact mechanism of hypoxic pulmonary vasoconstriction in the fetal pulmonary circulation is unclear. In isolated fetal pulmonary arteries [6], [7] or in intact fetal lambs [5], O2 modulates the production of both PGI2 and EDNO, two potent vasoactive substances that may underlie, in part, the responses of the developing pulmonary circulation to changes in oxygenation [5], [6], [7]. O2-related changes in pulmonary vascular resistance also are affected by pH; acidemia increases pulmonary vascular resistance and accentuates hypoxic vasoconstrictor responses [8].

One group of metabolites of arachidonic acid may be actively involved in the control of fetal pulmonary vascular resistance. Leukotrienes (LTs) C4 and D4, potent pulmonary vasoconstrictors synthesized from arachidonic acid by a 5′-lipoxygenase enzyme in pulmonary arterial tissue, may be tonically active in utero [9], [10], [11]. In fetal lambs, receptor blockade or inhibition of leukotriene synthesis increases pulmonary blood flow about 8-fold, i.e., to levels that approximate those achieved with normal ventilation after birth [12], [13]. These observations have suggested a physiologic role for leukotrienes in maintaining pulmonary vasoconstriction and, thereby, a low pulmonary blood flow in the fetus. Leukotrienes also have been isolated from tracheal fluid of fetal lambs, further suggesting that they may contribute to maintaining the high pulmonary vascular resistance [14], [15]. In some circumstances, leukotriene-induced vasoconstriction may be mediated by the production of thromboxane A2. However, in fetal lambs, inhibiting thromboxane synthesis does not affect pulmonary vascular resistance nor the response to leukotriene end-organ antagonism [16].

In addition to producing vasoconstrictors, the fetal pulmonary circulation actively and continuously produces vasodilating substances that modulate the degree of vasoconstriction under normal conditions and may play a more active role during periods of fetal stress. These substances are mainly endothelial-derived and include PGI2 and NO.

PGI2 is synthesized primarily in vascular endothelial cells, and vasodilates by activating adenylyl cyclase via receptor G protein-coupled mechanisms. Activation of adenylyl cyclase increases adenosine 3′,5′-cyclic monophosphate (cAMP), initiating a cascade that results in smooth muscle relaxation. Throughout gestation, a maturational increase in PGI2 production parallels the decrease in pulmonary vascular resistance in the fetal third trimester [6]. However, in vivo, prostaglandin inhibition does not markedly change resting pulmonary vascular resistance, calling into question the importance of basal PGI2 activity in mediating resting fetal pulmonary vascular tone [17].

NO is synthesized by the oxidation of the guanidino nitrogen moiety of l-arginine [18], with endothelial cell–derived NO synthetase (eNOS) catalyzing the reaction (Fig. 1). In response to stimuli such as shear stress, or receptor binding of specific vasodilators (endothelium-dependent vasodilators), NO is synthesized in the endothelial cell by activation of eNOS [19]. NO then is released, diffuses into adjacent vascular smooth muscle cells, and activates soluble guanylyl cyclase, the enzyme that catalyzes production of guanosine-3′-5′-cyclic monophosphate (cGMP) from guanosine-5′-triphosphate. This then initiates a cascade that results in smooth muscle relaxation [20] (Fig. 1). Production of NO and cGMP occurs in fetal, newborn, and adult pulmonary vasculature [21]. In the fetus, NO production also is stimulated by activation of ATP-dependent K+ channels [22], possibly stimulated by stretch or by increased shear forces on the pulmonary vascular endothelium. In fetal lambs, inhibiting NO synthesis increases resting pulmonary vascular resistance and inhibits the ventilation-induced fall in pulmonary vascular resistance [23], [24]. In addition, studies of intrapulmonary arteries and isolated lung preparations from sheep reveal maturational increases in NO-mediated relaxation during the late fetal and early postnatal period [25], [26], [27], [28], [29]. For example, in intrapulmonary arteries, basal NO production rises 2-fold from late gestation to 1 week postnatally, and another 1.6-fold from 1 to 4 weeks [27]. In rat lung parenchyma, both eNOS and soluble guanylyl cyclase gene expression rise during late gestation but fall postnatally [28], [29]. This maturational increase in NO and cGMP production parallels the dramatic fall in pulmonary vascular resistance at birth. These data indicate that NO activity mediates, in part, resting fetal pulmonary vascular tone as well as the fall in pulmonary vascular resistance during the transitional period. NO is released in response to acute pulmonary vasoconstricting stimuli, such as acute alveolar hypoxia or thromboxane administration, and together with the associated increase in cGMP probably modulates pulmonary hypertensive responses in the postnatal pulmonary circulation [30].

Endothelin-1 (ET-1), a 21-amino-acid polypeptide also produced by vascular endothelial cells, has potent vasoactive properties [31]. The hemodynamic effects of ET-1 are mediated by at least two distinct receptor populations, ETa and ETb. ETa receptors, located on vascular smooth muscle cells, likely are responsible for vasoconstriction, whereas ETb receptors, located on endothelial cells, likely are responsible for the vasodilation [32], [33] (Fig. 1). In the fetal and newborn pulmonary circulations, exogenous ET-1 predominantly vasodilates, mediated by ETb-receptor activation and NO release. However, in the juvenile and adult pulmonary circulations, the predominant effect is vasoconstriction, mediated via ETa receptor activation [34], [35]. This developmental alteration in the hemodynamic response to exogenous ET-1 is associated with developmental alterations in ET-1 receptor densities [36]. In fetal lambs, selective ETa receptor blockade produces only a small decrease in resting pulmonary vascular resistance, suggesting a minor role for basal ET-1-induced vasoconstriction in maintaining the high fetal pulmonary vascular resistance [37]. Plasma concentrations of ET-1 are increased at birth; however, in vivo data suggest that basal ET-1 activity does not play an important role in mediating the transitional pulmonary circulatory changes [38], [39].

Other vasoactive substances also may play a role in maintaining the high fetal pulmonary vascular resistance. Thromboxane A2, synthesized from arachidonic acid by the cyclo-oxygenase enzymes, is a vasoconstrictor, as is platelet activating factor. Both produce potent pulmonary vasoconstriction in newborn and adult animals. Several growth factors, particularly platelet derived growth factor (PDGF), which are involved in vascular smooth muscle growth and proliferation, also have vasoconstrictor effects. Whether any of these or other compounds yet to be defined contribute to maintaining the high pulmonary vascular resistance in the fetus is unknown.

At birth, with ventilation now assumed by the lungs, and the subsequent increase in arterial blood O2 tensions, pulmonary vascular resistance falls and pulmonary blood flow increases 8–10-fold to match systemic blood flow (300–400 ml/min/kg body weight).

This decrease in pulmonary vascular resistance is regulated by a complex and incompletely understood interplay between metabolic and mechanical factors, triggered by the ventilatory and circulatory changes that occur at birth. Physical expansion of the fetal lamb lung, without changing O2 tension, modestly increases pulmonary blood flow and decreases pulmonary vascular resistance [40]. A small proportion of this relates to replacement of fluid in the alveoli with gas, allowing unkinking of small pulmonary arteries, and to changes in alveolar surface tension, which exert a negative dilating pressure on the small pulmonary arteries [41]. Physical expansion of the lung also releases vasoactive substances such as PGI2, which increases pulmonary blood flow and decreases pulmonary vascular resistance in the fetal goat and lamb [42]. Inhibitors of prostaglandin synthesis (e.g., indomethacin or meclofenamic acid), which block PGI2 production, attenuate the fall in pulmonary vascular resistance with lung expansion, although not the changes that occur with oxygenation [43]. Thus, PGI2 – or perhaps, but less likely, another metabolite of arachidonic acid – plays some role in the decrease in pulmonary vascular resistance with the mechanical component (stretch) of ventilation at birth.

Other prostaglandins may also play a role in these circulatory changes. For example, PGD2 produces a greater pulmonary than systemic vasodilatation in newborn animals [44], [45], and this differential effect is lost 12–15 days after birth, when PGD2 produces pulmonary vasoconstriction. A similar pattern of response is seen with histamine, a modest pulmonary vasodilator in the immediate perinatal period but subsequently a pulmonary vasoconstrictor [46]. Both PGD2 and histamine are released from mast cells. In fetal rhesus monkeys, pulmonary mast cell numbers increase in late gestation, but after birth, these decrease markedly [47]. Therefore, the stimulus of lung expansion may cause mast cells to degranulate and release PGD2 and histamine, which contribute to the initial postnatal pulmonary vasodilatation.

Bradykinin, another endothelial dependent vasoactive agent, also is a potent vasodilator in the fetus [48]. Ventilating the lungs of fetal lambs with O2 or exposing the fetuses to hyperbaric O2 decreases the concentration of kininogen, the bradykinin precursor, with a concomitant increase in bradykinin concentrations [45]. Bradykinin stimulates both PGI2 and NO production in intact fetal lungs and in pulmonary vascular endothelial cells in culture, both of which would lead to vasodilatation [49]. However, bradykinin receptor blockade does not inhibit the decrease in pulmonary vascular resistance with O2 ventilation of the fetal lamb [50], calling into question the physiological role of bradykinin in the transition.

Ventilation of the fetus without changing oxygenation produces only partial pulmonary vasodilatation, whereas ventilation with air or O2 produces complete pulmonary vasodilatation. The exact mechanisms of O2-induced pulmonary vasodilatation during the transition remain unclear. The increase in alveolar or arterial O2 tension may decrease pulmonary vascular resistance, either directly by dilating the small pulmonary arteries, or indirectly by stimulating the production of vasodilator substances such as PGI2, bradykinin, or, more importantly, NO. Inhibition of NO synthesis markedly attenuates the increase in pulmonary blood flow due to either in utero ventilation with O2, or maternal hyperbaric O2 exposure [5], [51]. In utero ventilation without changing fetal PO2 increases eNOS gene expression in lung parenchyma of fetal lambs; this is further increased by ventilation with O2 [19]. Cultured fetal and newborn pulmonary endothelial cells show a maturational rise in NO production from late gestation to 4 weeks postnatally [26]; this NO production appears to be modulated by O2 [7]. Inhibition of NO synthesis prior to delivery attenuates the increase in pulmonary blood flow at birth [23], [52], suggesting an important role for NO during the transitional circulation.

The decrease in pulmonary vascular resistance with ventilation and oxygenation probably has at least two components. The first is a partial pulmonary vasodilatation caused by physical expansion of the lung and the production of prostaglandins (PGI2 and PGD2). This may be independent of oxygenation, and results in a modest rise in pulmonary blood flow and fall in pulmonary vascular resistance. The next component is maximal pulmonary vasodilatation associated with oxygenation, which is not necessarily dependent on prostaglandin production. This results in an increase in pulmonary blood flow and decrease in pulmonary vascular resistance to newborn values. This latter pulmonary vasodilatation is likely caused by the synthesis of NO, although the exact stimuli for NO production are not yet fully defined. However, it is highly probable that both components are necessary for the successful transition to extrauterine life. An additional mechanism by which vasodilatation may be produced is stimulation by increased shear forces, possibly related to the initial modest rise in flow, of endothelial cells to produce NO and perhaps also PGI2. It is possible that after the initial fall in pulmonary vascular resistance, due to another mechanism, this particular mechanism acts to maintain pulmonary vasodilatation.

More recently, two additional vasoactive substances, adrenomedullin and calcitonin gene-related peptide (CGRP), have been shown to be potent pulmonary vasodilators [53], [54]; however, their physiological role in the transitional period is not yet established. Both substances have similar profiles of effect, producing major and prolonged vasorelaxation in both the fetal and pre-constricted neonatal pulmonary vascular beds.

Although endothelin-1 is a potent fetal pulmonary vasodilator, and circulating levels of ET-1 are increased in the newborn period, in vivo data suggest that ET-1 activity does not play an important role in mediating the transitional changes in the pulmonary circulation [34], [38], [39], [55].

Control of the perinatal pulmonary circulation, therefore, probably reflects a balance between factors producing pulmonary vasoconstriction (low O2, leukotrienes, and other vasoconstricting substances) and those producing pulmonary vasodilatation (high O2, PGI2, NO, shear stress and other vasodilating substances). The dramatic increase in pulmonary blood flow with ventilation and oxygenation at birth reflects a shift from active pulmonary vasoconstriction in the fetus to active pulmonary vasodilatation in the newborn.

Section snippets

Condensation

Multiple vasoactive factors regulate pulmonary vascular resistance during the perinatal transition.

Acknowledgments

These studies were supported in part by US Public Health Service grant HL 40473.

References (55)

  • P.W. Shaul

    Nitric oxide in the developing lung

    Adv Pediatr

    (1995)
  • T. Nakamura et al.

    Immunoreactive endothelin concentrations in maternal and fetal blood

    Life Sci

    (1990)
  • M.A. Heymann et al.

    Control of fetal and neonatal pulmonary circulation

  • A.M. Rudolph et al.

    Circulatory changes during growth in the fetal lamb

    Circ Res

    (1970)
  • J. Rasanen et al.

    Role of the pulmonary circulation in the distribution of human fetal cardiac output during the second half of pregnancy

    Circulation

    (1996)
  • A.M. Rudolph

    Fetal and neonatal pulmonary circulation

    Ann Rev Physiol

    (1979)
  • M.H. Tiktinsky et al.

    Increasing oxygen tension dilates fetal pulmonary circulation via endothelium-derived relaxing factor

    Am J Physiol

    (1993)
  • P.W. Shaul et al.

    Oxygen modulation of pulmonary arterial prostacyclin synthesis is developmentally regulated

    Am J Physiol

    (1993)
  • P.W. Shaul et al.

    Oxygen modulates endothelium-derived relaxing factor production in fetal pulmonary arteries

    Am J Physiol

    (1992)
  • A.M. Rudolph et al.

    Response of the pulmonary vasculature to hypoxia and H+ ion concentration changes

    J Clin Invest

    (1966)
  • T. Ahmed et al.

    Does slow-reacting substance of anaphylaxis mediate hypoxic pulmonary vasoconstriction?

    Am Rev Respir Dis

    (1983)
  • D.P. Schuster et al.

    Leukotriene inhibitors do not block hypoxic pulmonary vasoconstriction in dogs

    J Appl Physiol

    (1987)
  • M.D. Schreiber et al.

    Leukotriene inhibition prevents and reverses hypoxic pulmonary vasoconstriction in newborn lambs

    Pediatr Res

    (1985)
  • J. Le Bidois et al.

    Piriprost: a putative leukotriene synthesis inhibitor increases pulmonary blood flow in fetal lambs

    Pediatr Res

    (1987)
  • S.J. Soifer et al.

    Leukotriene end organ antagonists increase pulmonary blood flow in fetal lambs

    Am J Physiol

    (1985)
  • H. Velvis et al.

    Leukotrienes C4, D4, and E4 in fetal lamb tracheal fluid

    J Dev Physiol

    (1990)
  • K.R. Stenmark et al.

    Leukotriene C4 and D4 in neonates with hypoxemia and pulmonary hypertension

    N Engl J Med

    (1983)
  • M. Clozel et al.

    Thromboxane is not responsible for the high pulmonary vascular resistance in fetal lambs

    Pediatr Res

    (1985)
  • F.C. Morin III et al.

    Indomethacin does not diminish the pulmonary vascular response of the fetus to increased oxygen tension

    Pediatr Res

    (1988)
  • R.M.J. Palmer et al.

    Vascular endothelial cells synthesize nitric oxide from l-arginine

    Nature

    (1988)
  • S.M. Black et al.

    Ventilation and oxygenation induce endothelial nitric oxide synthase gene expression in the lungs of fetal lambs

    J Clin Invest

    (1997)
  • R.R. Fiscus

    Molecular mechanisms of endothelium-mediated vasodilation

    Semin Thromb Hemost

    (1988)
  • J.-K. Chang et al.

    K+ channel pulmonary vasodilatation in fetal lambs: role of endothelial derived nitric oxide

    J Appl Physiol

    (1992)
  • S.H. Abman et al.

    Role of endothelium-derived relaxing factor during transition of pulmonary circulation at birth

    Am J Physiol

    (1990)
  • P. Moore et al.

    EDRF inhibition attenuates the increase in pulmonary blood flow due to oxygen ventilation in fetal lambs

    J Appl Physiol

    (1992)
  • T. Perreault et al.

    Maturational changes in endothelium-derived relaxations in newborn piglet pulmonary circulation

    Am J Physiol

    (1993)
  • R.H. Steinhorn et al.

    Developmental differences in endothelium-dependent responses in isolated ovine pulmonary arteries and veins

    Am J Physiol

    (1993)
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