Modulation of pulmonary vasomotor tone in the fetus and neonate

During early fetal development, PBF is limited by the paucity of pulmonary vessels. The number of fetal pulmonary vessels increases by an order of magnitude between mid-gestation and term. PVR remains high during the last trimester, however, and most of the right heart output is shunted across the ductus arteriosus and foramen ovale to the low-resistance systemic circuit. This is due in part to mechanical compression of pulmonary vessels by the fluid-filled, atelectatic lungs. In addition, fetal pulmonary vessels exhibit active tone.

In sheep, at 90–100 days of gestation (term 140 days) maternal hyperoxia increased fetal partial oxygen tension from approximately 20 to 175 mmHg, but had no effect on fetal PBF [1]. In contrast, after 115–120 days of gestation (ie at >75% term) an increase in fetal partial oxygen tension to 40–50 mmHg was associated with an almost 10-fold increase in PBF [1,2]. Thus, hypoxic pulmonary vasoconstriction (HPV) appears to develop during the third trimester when the number of pulmonary vessels increases.

Unlike the mature pulmonary circulation, the fetal pulmonary vasculature also appears to autoregulate flow through a myogenic response. This may explain why stimuli such as ductal compression, endothelium-dependent vasodilators, and increased oxygen tension cause only a transient increase in fetal PBF [3,4]. Finally, the balance between endogenous vasoconstrictor and vasodilator modulators contribute to the high PVR of the fetus.

At birth, PVR must decrease abruptly to accommodate 100% of cardiac output, thus allowing the lungs to assume their normal extrauterine gas exchange and metabolic functions. Several inter-related stimuli, including expansion of the lungs, increased oxygen tension and increased systemic vascular resistance, contribute to the decrease in PVR. Collectively, these stimuli, as well as the increase in levels of several endogenous vasoactive substances, lead to a marked increase in the ratio of vasodilator to vasoconstrictor modulators.

It has long been known that the initiation of rhythmic breathing causes vasodilatation, even in the absence of an increase in oxygen tension [28]. This is partly due to mechanical distension of the lungs, which increases vessel radius - a key physical determinant of vascular resistance. In addition, mechanical deformation of the lungs may directly enhance vasodilator modulator synthesis. Studies of neonatal animals found that ventilation caused an increase in prostacyclin synthesis [29] and cyclo-oxygenase inhibition prevented that normal decrease in PVR associated with rhythmic lung distension at birth [30,31]. NOS inhibition [32] and K_Ca channel inhibition [33] also blunt ventilation-induced pulmonary vasodilatation.

Increased oxygen tension at birth also reduces PVR, even in the absence of ventilation [28]. This is partly due to the loss of HPV. The mechanism of HPV remains uncertain, but several factors appear to contribute to the response. Recent studies of mature animal preparations [34,35] support the hypothesis that hypoxia causes ET_A-mediated inhibition of a K_V channel; this leads to vessel depolarization and calcium influx, resulting in vasoconstriction. The increase in oxygen at birth, together with the perinatal decrease in ET_A receptor message, probably contributes to decreased HPV at birth. However, it is noteworthy that K_Ca rather than K_V channels may play the depolarizing/hyperpolarizing role in response to changes in oxygen tension [27,36]. In addition to reducing HPV, the increased oxygen tension appears to enhance NO synthesis at birth [15]. A major role for NO in the transitional circulation is further supported by studies [19,32] that showed that NOS inhibition blunts the oxygen-induced decrease in PVR at birth.

Although the above paragraphs imply that oxygenation and ventilation have specific and direct effects on NO and prostacyclin synthesis, these stimuli, in conjunction with the recruitment and distension of the pulmonary vasculature by increased left atrial pressure, may act together through a flow-induced increase in shear stress. In the postnatal pulmonary circuit, increased shear stress in response to increased flow is a potent stimulus for endothelium-derived vasodilator modulator synthesis. This in turn establishes a positive feedback loop that enhances PBF until the increase in shear stress due to increased flow is offset by the decrease in shear stress due to increased vessel diameter. Distinguishing the role of shear stress, or indeed the effects of increased synthesis of other endogenous vasoactive substances (eg adenosine, bradykinin, etc), from the direct effects of oxygen and ventilatory movements remains an unfinished task.

Following the initial acute decrease in PVR at birth, there is a more gradual decline in resistance over the following days and weeks. Initially, this decrease in PVR reflects further recruitment and distension of the vascular bed, and spreading of the endothelial and vascular smooth muscle cells [37]. In addition, some studies [38] have identified a progressive decrease in arterial muscularization during the first few days of life. These developmental changes lead to a major decrease in PVR within days of birth [39]. Subsequently, lung growth and the increase in intra-alveolar vessel number lead to a more gradual reduction in PVR until adult levels are achieved.

During the early newborn period, however, an increase in PVR due to hypoxia or other pressor stimuli can lead to a resumption of right-to-left shunting across fetal cardiovascular channels. The resultant profound hypoxemia can lead to significant morbidity or death if pulmonary vasoconstriction is not reversed. Fortunately, despite evidence of increased pulmonary vascular muscularization in young newborn lungs, HPV appears to be more attenuated in younger than in older neonates [40,41,42,43]. Several factors may contribute to the neonatal defenses against pulmonary vasoconstriction. There is some evidence that hypoxia is not sensed as well by the younger newborn pulmonary vasculature [42], possibly because of the relative paucity of K_V2.1 channels [27]. Alternatively, the relative immaturity of neonatal pulmonary vascular smooth muscle may impair contractility [44]. Finally, there is considerable evidence that modulators of vasomotor tone attenuate vasoconstriction more in younger than in older newborns.

Prostacyclin synthesis is enhanced by hypoxia in arteries from 1- to 2-week-old newborns, but not in arteries from older newborns [22]. Furthermore, prostacyclin concentrations are higher in the perfusate of hypoxic 1-day-old than in 1-month-old lamb lungs [42]. In addition, prostaglandins E₁, E₂ and D₂ cause vasodilatation in hypoxic newborn lungs, but cause vasoconstriction in older animals [8]. Finally, cyclo-oxygenase inhibition enhances HPV more in lungs from lambs that are younger than 4 days old than in those from lambs older than 2 weeks [43]. Whether NO modulates pulmonary vasomotor tone more in younger than in older newborns is more controversial. In some studies of isolated vessels [18,45] endothelium-dependent vasodilatation was greater in arteries from younger than in those from older animals, whereas in others [46] it decreased with age. On the other hand, studies of isolated lungs suggest that both endothelium-dependent and -independent vasodilatation is greater in younger newborns [47], and NOS inhibition increased vasoconstriction more in lungs from younger than in those from older newborns [48].

Not only does acute inhibition of vasodilator modulators increase basal PVR and enhance vascular reactivity in normal newborn lungs, but also there is evidence that an imbalance between vasoconstrictor and vasodilator modulators may contribute to the pathogenesis of various forms of neonatal pulmonary hypertension. The syndrome of persistent pulmonary hypertension of the newborn (PPHN) is characterized by abnormally increased pulmonary vascular muscularization and severe neonatal pulmonary hypertension in the absence of other pulmonary or cardiac disease. Studies conducted during the 1970s and 1980s [49] found that chronic in utero cyclo-oxygenase inhibition could result in the anatomic and physiologic features of PPHN. More recently, a study of newborn lambs [50] showed that in utero infusion of a NOS inhibitor for 10 days mimicked the physiologic, but not the anatomic features of PPHN. In addition, chronic fetal ET_B receptor inhibition, which results in unopposed ET_A-mediated constriction, led to pulmonary hypertension [51]. Conversely, both acute and chronic intrauterine pulmonary hypertension due to ductal compression led to impaired endothelium-dependent vasodilatation [52,53] and reduced channel expression [54]. Chronic hypoxia K_Ca during the newborn period also leads to pulmonary hypertension, associated with decreased NOS protein and message, and impaired endothelium-dependent vasodilatation [55,56].

The pathophysiology of PPHN is not only dependent on a deficiency in the vasodilator modulators, but may also result from an excess of vasoconstrictor modulators. In one study of infants with PPHN [57], leukotriene C₄ and leukotriene concentrations were higher than in D₄ neonates without PPHN. Lung thromboxane A₂ concentrations were also higher in an ovine model of PPHN than in control lambs [58]. Finally, serum endothelin-1 concentrations were higher in infants with PPHN [59].

Although modulators of pulmonary vasomotor tone appear to contribute to elevated fetal pulmonary vasomotor tone, the decrease in PVR at birth, and the defenses against pulmonary vasoconstriction during early life, many questions remain. Is there sufficient redundancy among modulator classes that the loss of one can be compensated for by an increase in another? Do the reported differences in modulator activity between arteries and veins mean that all modulators must be synthesized in order to achieve normal development [17,60]? What do apparent interspecies differences in modulator activity imply for the prevention and therapy of neonatal pulmonary hypertension in humans? Can the loss of modulator activity be identified and treated in utero? Future studies must address these and other questions in order to gain a better understanding of the physiology and pathophysiology of pulmonary vasomotor tone in the fetus and young neonate.