STUDY QUESTION What is the physiological extent of vascular remodelling in and trophoblast plugging of the uterine circulation across the first half of pregnancy? SUMMARY ANSWER All levels of the uterine vascular tree (arcuate, radial and spiral arteries (SAs)) dilate ∼2.6- to 4.3-fold between 6 and 20 weeks of gestation, with significant aggregates of trophoblasts persisting in the decidual and myometrial parts of SAs beyond the first trimester. WHAT IS KNOWN ALREADY In early pregnancy, endovascular trophoblasts form ‘plugs’ in the SAs, transiently inhibiting blood flow to the placenta, whilst concurrently the uterine vasculature undergoes significant adaption to facilitate increased blood delivery to the placenta later in gestation. These processes are impaired in pregnancy disorders, but quantitative understanding of the anatomical changes even in normal pregnancy is poor. STUDY DESIGN, SIZE, DURATION Serial sections of normal placentae in situ (n = 22) of 6.1–20.5 weeks of gestation from the Boyd collection and Dixon collection (University of Cambridge, UK) were digitalized using a slide scanner or Axio Imager.A1 microscope. PARTICIPANTS/MATERIALS, SETTING, METHODS Spiral (n = 45), radial (n = 40) and arcuate (n = 39) arteries were manually segmented. Using custom-written scripts for Matlab® software, artery dimensions (Feret diameters; major axes; luminal/wall area) and endovascular trophoblast plug/aggregate (n = 24) porosities were calculated. Diameters of junctional zone SAs within the myometrium (n = 35) were acquired separately using a micrometre and light microscope. Decidual thickness and trophoblast plug depth was measured using ImageJ. MAIN RESULTS AND THE ROLE OF CHANCE By all measures, radial and arcuate artery dimensions progressively increased from 6.1 to 20.5 weeks (P < 0.01). The greatest increase in SA calibre occurred after 12 weeks of gestation. Trophoblast aggregates were found to persist within decidual and myometrial parts of SA lumens beyond the first trimester, and up to 18.5 weeks of gestation, although those present in the second trimester did not appear to prevent the passage of red blood cells to the intervillous space. Trophoblasts forming these aggregates became more compact (decreased in porosity) over gestation, whilst channel size between cells increased (P = 0.01). Decidual thickness decreased linearly over gestation (P = 0.0003), meaning plugs occupied an increasing proportion of the decidua (P = 0.02). LARGE SCALE DATA N/A. LIMITATIONS, REASONS FOR CAUTION Although serial sections were assessed, two-dimensional images cannot completely reflect the three-dimensional properties and connectivity of vessels and plugs/aggregates. Immersion-fixation of the specimens means that vessel size may be under-estimated. WIDER IMPLICATIONS OF THE FINDINGS Uterine vascular remodelling and trophoblast plug dispersion is a progressive phenomenon that is not completed by the end of the first trimester. Our quantitative findings support the concept that radial arteries present a major site of resistance until mid-gestation. Their dimensional increase at 10–12 weeks of gestation may explain the rapid increase in blood flow to the placenta observed by others at ∼13 weeks. Measured properties of trophoblast plugs suggest that they will impact on the resistance, shear stress and nature of blood flow within the utero-placental vasculature until mid-gestation. The presence of channels within plugs will likely lead to high velocity flow streams and thus increase shear stress experienced by the trophoblasts forming the aggregates. Quantitative understanding of utero-placental vascular adaptation gained here will improve in silico modelling of utero-placental haemodynamics and provide new insights into pregnancy disorders, such as fetal growth restriction. STUDY FUNDING/COMPETING INTEREST(S) This work was supported by a Royal Society Te Aparangi Marsden Grant [18-UOA-135]. A.R.C. is supported by a Rutherford Discovery Fellowship [14-UOA-019]. The authors have no conflict of interest to declare.
The endothelial glycocalyx layer (EGL) is a macromolecular layer that lines the inner surface of blood vessels. It is believed to serve a number of physiological functions in the microvasculature, including protection of the vessel walls from potentially harmful levels of fluid shear, as a molecular sieve that acts to regulate transendothelial mass transport, and as a transducer of mechanical stress from the vessel lumen. To best fulfil some of its roles, it has been suggested that the EGL redistributes, so that it is thickest at the cell–cell junctions. It has also been suggested that the majority of mechanotransduction occurs through the solid phase of the EGL, rather than via its fluid phase. The difficulties associated with measuring the distribution of the EGL in vivo make these hypotheses difficult to confirm experimentally. Consequently, to gauge the impact of EGL redistribution from a theoretical standpoint, we compute the flow through a porous-lined microvessel, the endothelial surface of which has been informed by confocal microscopy images of a postcapillary venule. Following earlier studies, we model the poroelastohydrodynamics of the EGL using biphasic mixture theory, taking advantage of a recently developed boundary integral representation of these equations to solve the coupled poroelastohydrodynamics using the boundary element method. However, the low permeabilities of the EGL mean that viscous effects are confined to thin layers, thereby also enabling an asymptotic treatment of the dynamics in this limit. In this asymptotic regime, we also consider a two-layer Stokes flow model for the lumen flow to approximate the effect of red blood cells within the lumen. We demonstrate that redistribution of the EGL can have a substantial impact upon microvessel haemodynamics. We also confirm that the bulk of the mechanical stress is indeed carried through the solid phase of the EGL.
In pregnancy, fetal growth is supported by its placenta. In turn, the placenta is nourished by maternal blood, delivered from the uterus, in which the vasculature is dramatically transformed to deliver this blood an ever increasing volume throughout gestation. A healthy pregnancy is thus dependent on the development of both the placental and maternal circulations, but also the interface where these physically separate circulations come in close proximity to exchange gases and nutrients between mum and baby. As the system continually evolves during pregnancy, our understanding of normal vascular anatomy, and how this impacts placental exchange function is limited. Understanding this is key to improve our ability to understand, predict, and detect pregnancy pathologies, but presents a number of challenges, due to the inaccessibility of the pregnant uterus to invasive measurements, and limitations in the resolution of imaging modalities safe for use in pregnancy. Computational approaches provide an opportunity to gain new insights into normal and abnormal pregnancy, by connecting observed anatomical changes from high-resolution imaging to function, and providing metrics that can be observed by routine clinical ultrasound. Such advanced modeling brings with it challenges to scale detailed anatomical models to reflect organ level function. This suggests pathways for future research to provide models that provide both physiological insights into pregnancy health, but also are simple enough to guide clinical focus. We the review evolution of computational approaches to understanding the physiology and pathophysiology of pregnancy in the uterus, placenta, and beyond focusing on both opportunities and challenges.
Frequency response of cantilever beams immersed in compressible fluids with applications to the atomic force microscope J. Appl. Phys. 106, 094904 (2009); 10.1063/1.3254191Frequency response of cantilever beams immersed in viscous fluids with applications to the atomic force microscope: Arbitrary mode order
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