Antenatal hypoxia and pulmonary vascular function and remodeling

Abstract

This review provides evidence that antenatal hypoxia, which represents a significant and worldwide problem, causes prenatal programming of the lung. A general overview of lung development is provided along with some background regarding transcriptional and signaling systems of the lung. The review illustrates that antenatal hypoxic stress can induce a continuum of responses depending on the species examined. Fetuses and newborns of certain species and specific human populations are well acclimated to antenatal hypoxia. However, antenatal hypoxia causes pulmonary vascular disease in fetuses and newborns of most mammalian species and humans. Disease can range from mild pulmonary hypertension, to severe vascular remodeling and dangerous elevations in pressure. The timing, length, and magnitude of the intrauterine hypoxic stress are important to disease development, however there is also a genetic-environmental relationship that is not yet completely understood. Determining the origins of pulmonary vascular remodeling and pulmonary hypertension and their associated effects is a challenging task, but is necessary in order to develop targeted therapies for pulmonary hypertension in the newborn due to antenatal hypoxia that can both treat the symptoms and curtail or reverse disease progression.

Fig. (1). The pulmonary arterial wall in normal and antenatal hypoxia diseased lung

In a normal lung the vessel wall and smooth muscle layer is thin. The endothelium lines the lumen of the artery and in distal arteries there is no smooth muscle or elastic lamina. With antenatal hypoxia there can be thickening of the smooth muscle layer that impinges on the arterial lumen along with alterations in myocyte reactivity, as well as disruption of endothelial cell structure with loss of barrier function. These changes are manifested through a number of disruptions involving transcriptional regulators, signaling pathways, and ion channels. The figure summarizes the major components that are discussed in this review.

Fig. (2). Pulmonary vasoconstriction in the fetus is a highly coordinated process

A combination of low oxygen tension and humoral mediators constrict the lung in-utero. The mechanisms associated with hypoxic-induced pulmonary vasoconstriction remain controversial, but a combination of activation of L-type Ca²⁺ channels, ryanodine receptors, rho-kinase, non-selective cation channels, and inhibition of K⁺ channels are each important in contraction of pulmonary arteries from adult animals. Pulmonary vascular resistance of the fetal lung is thought to be maintained at a high level due to increased vasoactive agonists, including elevated ET-1 levels. The high ET-1, released from the vascular endothelium, works through a Gq coupled receptor to activate a number of intracellular signaling pathways that lead to smooth muscle cell contraction through simultaneous activation of MLCK and inhibition of MLCP. Solid line with arrow: Activation pathway, Dashed line with bar: Inhibition pathway.

Fig. (3). Pulmonary vasodilation at birth is orchestrated

Mechanical forces due to breathing, combined with increases in vascular flow and blood oxygenation act to dilate vessels of the lung. Vasodilatory substances, shear stress and membrane stretch work together to increase prostacyclin (PGI₂), nitric oxide (NO) production, and other pathways defined broadly as endothelial derived hyperpolarizing factors (EDHF) that have not been fully examined in the fetus. Signaling molecules released from the endothelium act in concert with epinephrine (Epi) and other neuro-humoral substances to increase Protein Kinase A and G activity (PKA and PKG). These kinases phosphorylate a wide array of different substrates to impinge on vascular contraction. As discussed, antenatal hypoxia depresses a number of these vasodilatory signals which leads to maintenance of vasoconstriction. Solid line with arrow: Activation pathway, Dashed line with bar: Inhibition pathway.

Fig. (4). High-altitude travel is accompanied by reduced ambient PO₂

Human infants are born at altitudes ranging from sea level to about 5,100 m. We highlight work from two high altitude field stations that are at elevations similar to high-altitude cities in Tibet and Bolivia. This graph is based on Boyle's law, where the partial pressure of a gas is inversely related to the altitude.

Fig. (5). High-altitude decreases maternal and fetal arterial PO₂

Values were obtained for sheep at altitudes simulating the ambient PO₂ for the Barcroft facilities at the White Mountain Research Station [WMRS]. The maternal PaO₂ is considerably higher than that of the fetus at low altitude and more greatly influenced by exposure to high altitude.

Fig. (6). Relationship between fetal brachial artery PO₂ and oxyhemoglobin saturation (HbO₂) from fetal sheep

Blood samples were collected from chronically instrumented fetuses while the ewe was breathing an FiO₂ of 0.12 to 0.21, or within three hours after cesarean section followed by mechanical ventilation with FiO₂ adjusted to achieve PaO₂ ranging between 25 and 50 mmHg. All lambs had PaCO₂ and pH within normal range. Dashed lines denote brachial PaO₂ and HbO₂ levels for fetal lambs near sea level (Loma Linda) or at high altitude (Barcroft facilities at the White Mountain Research Station [WMRS]). Measurements were made in fetal lambs that were 127 to 130 days gestation.

Fig. (7). Acclimatization continuum for perinatal hypoxia-induced lung structure and function responses amongst commonly studied species

As discussed in the text, there is not only a wide degree of variance between individual species but also there can be variability within species. Llamas and cows are on opposite ends of the spectrum and based on the published studies they have lower variability than rats, dogs, or humans. The responses of newborn sheep are less severe than rodents or cows but the dysfunctions are similar to those found in human infants. The length and placement of the bars provides a subjective ranking based on the amalgamation of information provided in the text. We considered the influence of antenatal hypoxia on: decrease of lung diffusion capacity, elevation in pulmonary artery pressures and subsequent hypertrophy of the right ventricle, muscularization of the small vessels and overall vascular remodeling, increased HPV response, increases or decreases in the reactivity of the vessels to agonists as well as endothelial mediated vessel dilation, evidence of intrauterine growth restriction, and survival.