Uterine remodelling bleeds into the second trimester: digitalised historic samples illuminate vascular adaptation to pregnancy Free

Introduction

Remarkable cardiovascular changes occur during pregnancy, including increases in heart rate, stroke volume and plasma volume, which ultimately channel blood through the uterine artery at up to 10 times the non-pregnant rate (Palmer et al., 1992). Adaptation of the uterine vascular tree is required to accommodate this volume and regulate its flow to the placenta in order to prevent haemorrhage and optimise nutrient and gas exchange. Vascular changes occur gradually, matching the development of the placenta to a fully perfused state by the end of the first trimester. Indeed, much is known about the remodelling of the tortuous terminal arteries of the endometrial vascular bed, termed spiral arteries, as specimens can be made available from first trimester and term tissue. These show direct structural remodelling of spiral arteries by placenta-derived trophoblast that allows for high volume perfusion of the exchange surface of the placenta at a low flow rate (Aplin et al., 2020). However, the radial and arcuate arteries in the upper uterine vascular tree play a critical role in controlling blood flow to the maternal–foetal interface and yet our knowledge of their adaptation to pregnancy is extremely limited. Vascular pathophysiology underlies the major obstetric complications pre-eclampsia, foetal growth restriction and stillbirth (Brosens et al., 2011). Moreover, these disorders are more common in populations treated with ART (Qin et al., 2016), thus understanding vascular adaptation to pregnancy is imperative to improving both fertility and obstetric care.

In this issue of Human Reproduction, Allerkamp et al. (2020) quantified uterine vascular anatomy across the first half of pregnancy through semi-automated processes after digitalising historic early pregnancy uterine tissue samples of the Boyd and Dixon collections at the University of Cambridge, UK. This approach yielded the first high-resolution quantification of upper vasculature changes from weeks 6 to 20 of pregnancy, revealing striking dilation of these vessels in a coordinated manner running well into the second trimester. In addition, trophoblast aggregates, or ‘plugs’, which restrict maternal blood flow to the nascent first-trimester placenta, were found to be more extensive and complex in structure and to last longer into the second trimester than had been thought. These analyses significantly advance our understanding of how structural changes over the whole uterine vascular tree regulate blood flow to the placenta in early pregnancy, and will allow for better haemodynamic modelling of uterine vasculature to help in the diagnosis and treatment of obstetric pathologies.

Trophoblast plug structure and longevity suggests a haemodynamic role into the second trimester

The initial invasive process of embryo implantation is mediated by a collective mass of trophoblast but as the placental villous structure develops, extra-villous trophoblast (EVT) break free and invade deeply into the endometrial tissue and spiral arteries. The full effect of trophoblast aggregates in spiral arteries has been a controversial topic in early pregnancy (Pijnenborg et al., 2006), with a simple plugging role to allow for placental maturation usurped in the last two decades by a more complex model whereby plug porosity progressively increases from permitting some plasma flow mid-first trimester to allowing limited whole blood flow prior to the second trimester (Roberts et al., 2017).

Allerkamp et al. substantially expand on the parameters in these contemporary models by showing plugs to be up to twice as long as previously thought, progressively porous up to week 12, and persistent right up to week 20. This evidence shores up the idea that trophoblast plugs regulate the onset of blood flow to the placenta around the 10- to 12-week mark without detaching completely, while also demonstrating that these aggregates likely contribute to utero-placental haemodynamics well beyond the first trimester. As well as providing essential quantities for in-silico modelling of trophoblast plug function, these beautiful visualisations of native aggregates should inspire in-vitro modelling of EVT interactions with each other, with endothelial cells and with fluid flow. Taking this approach with modern culture techniques, including trophoblast stem cells, extracellular scaffolds and microfluidics, could provide experimental systems to test how trophoblast plugs work.

Coordinated remodelling of radial and arcuate arteries may be critical to a healthy pregnancy

Despite poor utero-placental perfusion being ascribed to insufficient remodelling of spiral arteries in pre-eclampsia, in many patients, these vessels often appear normal (Lyall et al., 2013). There is evidence that failed adaptation of the radial, arcuate and uterine arteries contributes to obstetric pathology (Ong et al., 2005), but much less is known about these vessels of the upper uterine vascular tree in pregnancy. The first quantified description of arcuate and radial arteries over the first half of pregnancy, as described by Allerkamp et al., confirm that the radial arteries, together with the adjoining proximal spiral arteries, provide a major point of resistance to blood flow in the first trimester. In addition, they show that this could be driven by delayed luminal expansion in the early second trimester compared to mid-late first-trimester expansion in the upper arcuate arteries. Such coordination of upper arterial remodelling together with changes to plug structure across the trimester boundary may be crucial to provide the optimal haemodynamics to initiate perfusion of the maternal–foetal interface through fully remodelled spiral arteries. It is tempting to speculate that failed coordination of dilation from the upper to lower vascular tree, leading to malperfusion or mistimed initiation of blood flow to the placenta, could be the driver of pathology in some cases.

What signals drive vascular remodelling in pregnancy?

Hormonal signals from the placenta and blood flow changes induced by placental development are thought to drive upper uterine and systemic vascular adaptation. However, despite their importance to obstetric disease, the precise biological mechanisms are not well characterised. Correlations between placental hormones and obstetric vascular pathologies have highlighted hCG, relaxin, vascular endothelial growth factor and placental growth factor as candidate mediators of local and systemic vascular remodelling (Osol et al., 2019). The quantitative assessments of Allerkamp et al. provide further evidence that outward hypertrophic remodelling of vessels is the mode of change induced by hormonal and haemodynamic candidates, although improved imaging and hormonal analysis together with ex-vivo, in-vitro and animal model studies will be required to unravel the downstream signalling networks. Combined with early diagnosis, targeting these networks could provide treatments to prevent the development of obstetric disorders for which the only current treatment is early delivery.

The importance to ART of understanding pregnancy physiology

Obstetric pathologies can have lifelong programming effects on both mother and baby; pre-eclamptic mothers are at greater risk of cardiovascular disease later in life, while their babies are also exposed to the long-term programming effects of in-utero stress and pre-term delivery (Lane-Cordova et al., 2019). Sadly, these terrible diseases are more common in ART populations. As ART aims to facilitate pregnancy and the birth of a healthy baby without causing harm, more basic science research is needed to illuminate the path from implantation to labour so as to highlight how ART interventions may increase the risk of pregnancy complications. Allerkamp et al. go some significant way to establishing the blueprints of vascular adaptation to pregnancy, and showcasing this basic physiology study serves to indicate how much more needs to be done to understand the fundamental biology of human pregnancy.

Data availability

No new data are reported in this manuscript.

Funding

No funding directly supported the preparation of this manuscript.

Conflict of interest

None to declare.

References