Blood pressure in the chronically hypoxaemic fetus is regulated by α‐adrenergic receptors on the peripheral vasculature

Chronic hypoxaemia and intrauterine growth restriction (IUGR) during fetal development are known to increase the risk of death from cardiometabolic disease later in life. Growth restricted fetuses are susceptible to the development of hypertension, a risk factor associated with cardiovascular disease. IUGR affects a startling 5–10% of the population; thus, it is crucial to understand the mechanisms that underlie the increased risk of hypertension and the altered blood pressure (BP) regulation in these fetuses. In late gestation fetal sheep, the response to acute hypoxaemia involves the redirection of blood flow towards the heart brain, and adrenals in a preferential manner at the cost of the intestines and extremities. Chronic hypoxaemia associated with placental insufficiency and subsequent IUGR differs in that brain sparing still occurs; however, blood flow is not redirected, suggesting that the fetal response depends on the length of the hypoxaemic conditions on top of the severity and gestational timing of hypoxaemia. Although acute hypoxaemia has been investigated in great detail, the adaptations and mechanisms of chronic hypoxaemia remain poorly understood. A key fetal adaptation associated with BP maintenance in the chronically hypoxaemic IUGR fetal sheep is the increased circulation of the catecholamine noradrenaline (NA) in the blood. NA can be released via neural stimuli to the adrenal medulla or by sympathetic nerve terminals onto α-adrenergic receptors of the peripheral vasculature. There is a possibility that a reduction of neural input to the medulla to normalize NA levels at birth could be an option for preventing hypertension in IUGR fetuses when stable oxygen levels have established. However, there is also literature proposing that hyperinnervation of the peripheral vasculature is the key player in BP regulation in the chronically hypoxaemic fetus. Further research is warranted to determine the roles of both of these pathways in regulating blood pressure in chronically hypoxaemic IUGR fetal sheep. In a recent paper published in The Journal of Physiology, Darby et al. (2021) employed pharmaceutical blockades in an in vivo study to explore the involvement of both the adrenal medulla and hyperinnervation of the peripheral vasculature with respect to the regulation of BP in chronically hypoxaemic fetuses. Darby et al. (2021) showed that the post-ganglionic blockade results in the same BP response in both IUGR and control fetuses. Notably, IUGR fetuses experience a greater drop in mean arterial pressure (MAP) after α-adrenergic receptor blockade and an inverse relationship exists between this drop and fetal . Moreover, this study provided additional evidence that, although chronically hypoxaemic fetuses are normotensive, maintenance of basal arterial pressure heavily relies on α-adrenergic innervation of the peripheral vasculature. The inclusion of two gestational ages (GA) as opposed to one was a strength of the study because the data obtained suggests that the degree to which MAP regulation relies on α-adrenergic receptor stimuli increases over gestation. Darby et al. (2021) implemented a surgical procedure to reduce the number of placental attachment sites in the uterus of ewes. This procedure was outlined in several previous studies and entailed the removal of endometrial caruncles prior to pregnancy. As a result, any fetuses carried by these ewes experienced placental restriction, chronic hypoxaemia and IUGR (Dyer et al. 2009). After these ewes became pregnant and between 110 and 126 days GA, polyvinyl catheters were inserted into the fetal jugular vein for drug infusion and in the carotid and femoral arteries to allow for the measurement of blood gas levels, heart rate (HR) and BP. The two notable blood gas measurements in this study were the partial pressures of oxygen () and oxygen saturation (). Post ganglionic and α-adrenergic receptor blockades were induced using two different drugs. For the former, a nicotinic acetylcholine receptor antagonist known as hexamethonium was used, which works by disrupting neural stimuli to the adrenal medulla. For the latter, the α-adrenergic receptor antagonist drug by the name of phentolamine was used to block receptors on the peripheral vasculature. Both drugs were injected into the fetal jugular vein on different days within two gestational age brackets: 116–120 days and 129–131 days. Ewes were then humanely killed at 131—137 days GA with a barbiturate overdose and the fetuses were delivered and weighed. The results showed that IUGR fetuses weighed significantly less than controls at both gestational ages. With respect to fetal blood gas measurements, and were significantly diminished in IUGR fetuses compared to controls at both GAs. A closer look at the results from the pharmaceutical receptor blockades leads to the first key finding, which was that the BP response to the post-ganglionic blockade did not differ between IUGR and control fetuses. This was evident because hexamethonium did not cause a change in fetal HR and it decreased BP and MAP equally in controls and IUGR fetuses at both GAs. Conversely, phentolamine caused an increase in HR at both GAs. It also decreased BP measurements in the same manner as hexamethonium for the early GA; however, for the later GA, the decrease observed in BP and MAP were far greater in IUGR fetuses than in controls. Thus, it is apparent that, out of the two blockers used, the IUGR fetuses showed a more prominent maximum response to the α-adrenergic blockade compared to controls. On the level of the vasculature, the study clearly showed that the drop in MAP was greater in IUGR fetuses after α-adrenergic receptor blockade. Nonetheless, Darby et al. (2021) did not stop there; they went on to show that there was a dependence of the α-adrenergic receptor blockade on fetal blood oxygen levels. Upon drug injection, the maximum response in MAP was compared with fetal levels. Using linear regression, it was determined that an inverse relationship exists between the decrease in MAP response to α-adrenergic receptor blockade and fetal . Lower levels correlate with a larger drop in MAP. By contrast, no relationship was seen between the MAP drop caused by the post-ganglionic blockade and average fetal at either GA. In the case of acute hypoxaemia, brain sparing occurs as a result of peripheral vasoconstriction. This cardiovascular response is governed by NA derived from the adrenal medulla. This was confirmed in a study where destruction of the adrenal medulla lead to reduced vasoconstriction (Jones et al. 1988). For this response to occur, carotid bodies must sense a decrease in . However, when it comes to chronic hypoxaemia, this chemoreflex of the carotid bodies may not occur. Interestingly, previous studies that used the same PR model (Danielson et al. 2005) for chronic hypoxaemia noted increased fetal NA levels as soon as blood was collected at around 90 days. Additionally, as seen in the study by Darby et al. (2021), the fetuses exhibited normal BP and relied more heavily on α-adrenergic stimuli to regulate BP as opposed to the adrenal medulla regulation seen in acute hypoxaemia. These findings confirmed the link between the sympathetic nervous system and cardiovascular adaptation to chronic hypoxaemia. The vasoconstriction of the peripheral vasculature seen in hypoxaemic fetuses can be caused by several sources of NA travelling through the bloodstream. The results obtained by Darby et al. (2021) do not provide support for NA derived from the adrenal medulla being responsible for BP regulation in chronically hypoxaemic fetuses. This was evident when they showed that the decrease in MAP was equivalent for both IUGR and control fetuses at both GAs with the hexamethonium induced post-ganglionic blockade. A hypothesis proposed by Simonetta et al. (1997) suggests that a greater number of sympathetic nerve terminals results in the secretion of higher volumes of NA. This hypothesis was further backed by a study in chicken embryos, which showed evidence of arterial hyperinnervation upon exposure to chronically hypoxaemic conditions (Ruijtenbeek et al. 2000). The study on embryos also observed that the density of sympathetic nerves was governed by fetal oxygenation status. These findings parallel the results from this study and an older paper by Danielson et al. (2005), when phentolamine induced α-adrenergic blockade was used. The chronically hypoxaemic fetuses experienced a greater decrease in MAP than the controls and, using regression, it was shown that a decrease in MAP is associated with fetal oxygenation levels. Danielson et al. (2005) carried out substantial work to reach these conclusions and the work completed by Darby et al. further elaborated these results by comparing the BP response both across gestation and also when different sources of NA are blocked. It was shown that reliance on α-adrenergic receptor stimuli for MAP regulation builds up over gestation. In sum, Darby et al. (2021) have demonstrated that the cardiovascular response for chronic hypoxaemia is regulated by α-adrenergic receptors on the peripheral vasculature. Additionally, they have shown that the degree to which BP regulation relies on α-adrenergic receptor stimuli depends on fetal oxygenation status. Also, unlike acute hypoxaemia, which relies on neural stimuli to the adrenal medulla to regulate BP, chronically hypoxaemic fetuses experience sympathetic hyperinnervation of the peripheral vasculature. These findings attest that adjusting NA secretion at birth when oxygen levels have normalized will not help in preventing hypertension in fetuses that are born growth restricted. These fetuses have more sympathetic nerve terminals on their peripheral vasculature and, as such, rely more heavily on α-adrenergic innervation to regulate blood pressure. No competing interests declared. Sole author. None. I would like to acknowledge that I was unable to cite all relevant sources as a result of reference limitations.

Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.