Dynamic glucose enhanced MRI of the placenta in a mouse model of intrauterine inflammation
Introduction
Glucose, as the primary substrate for energy production and a mediator in many biosynthetic processes [1,2], is crucial to fetal development [3]. The placental capacity to deliver glucose to the fetus is an important indicator of placental health. Placental utilization of glucose has been investigated for many years, for example, malfunction of glucose transporters was found to be a contributor in a range of placental disorders, such as preeclampsia [4,5] and intrauterine growth restriction (IUGR) [6,7]. However, such studies were performed using in vitro approaches in excised placental tissue slices, isolated placental villi, or perfused placenta [8]. Clinical measures are mostly limited to biochemical sampling of the maternal blood, e.g., hormonal factors in a glucose tolerance test [9]. Direct in vivo assessment of glucose utilization in the placenta would be optimal and clinically useful, but such techniques are currently not available.
Magnetic resonance imaging (MRI) has become an increasingly important imaging tool to evaluate placental anatomy and function, in addition to ultrasound [10], especially in complex cases. For example, dynamic contrast enhanced (DCE) MRI [11,12], arterial spin labeling (ASL) [13,14], and intravoxel-incoherent motion (IVIM) MRI [[15], [16], [17], [18]] have been adopted to measure placental perfusion; and T2 and T2* mapping [[19], [20], [21]], and BOLD MRI [22,23] have shown sensitivity to placental oxygenation. Traditionally, the detection of glucose concentration and metabolic rate is performed by MR spectroscopy [[24], [25], [26], [27], [28], [29], [30]], which is a slow and low-resolution technique. Recently, it was demonstrated that glucose in brain and body organs can be monitored with Chemical Exchange Saturation Transfer (CEST) MRI [31,32], as well as relaxometry-based MRI contrasts, such as T1ρ [33,34] and T2-weighted MRI [35]. Briefly, CEST MRI utilizes radiofrequency (RF) irradiation to selectively saturate exchangeable protons in the low-concentration solutes typically only measurable with MRS. This saturation is subsequently transferred to water protons through proton exchange, replaced by non-saturated protons and again saturated. Because of the rapid exchange of these protons, the process is repeated many times within a single MRI detection, resulting in the building up of a reduction in water signal intensity. Thus, CEST MRI can amplify the signal from low-concentration metabolites to be detected via the abundant bulk water protons, in a manner proportional to the concentration of these agents. By tuning the CEST frequency to the hydroxyl protons on d-glucose, called glucoCEST MRI, we and others have shown the detection of the presence of d-glucose or its derivatives using the MRI signal in vivo [[36], [37], [38]]. The measurement of time-resolved changes of glucoCEST MRI signal after a bolus intravenous infusion of glucose, referred to as Dynamic Glucose Enhanced (DGE) MRI, reports the changes in glucose concentration in biological tissues and thus contains information on glucose delivery, transport and metabolic kinetics. DGE MRI using continuous-wave (CW) or pulsed CEST has been used to image the glucose uptake in tumors and other tissues both in animals [[36], [37], [38], [39], [40], [41]] and humans [42]. Feasibility of DGE in the placenta is not yet known.
An On-Resonance Variable Delay Multiple Pulse (onVDMP) technique [43] was recently developed to further enhance the sensitivity of glucoCEST. In contrast to CW-CEST that targets a single off-resonance frequency, the onVDMP method efficiently labels a range of fast-exchanging protons, covering multiple resonance frequencies of the five hydroxyl protons with exchange rates between 3 and 6 kHz. It has been demonstrated that DGE signal changes in the brain detected by onVDMP were about two times higher than those measure by CW-CEST [44]. In this study, we investigated the feasibility of onVDMP-based DGE to monitor glucose kinetics in normal and injured placentae. The study was performed in an established mouse model of intrauterine inflammation (IUI) [45,46], in which placental and fetal injury was induced by excessive maternal production of inflammatory cytokines due to lipopolysaccharide (LPS) administration. This model mimics the most common clinical scenario associated with preterm birth. In this model, we have previously identified acute maternal vascular malperfusion (MVM) with IVIM and immunohistochemistry measurements in the placenta [47], and thus, the model serves as an ideal test bed for potential clinical translation of DGE MRI to assess placental function. In this study, we performed DGE MRI to examine the time-resolved placental response to a glucose challenge in LPS-exposed placentae, in comparison with the controls.
Section snippets
Materials
All experimental procedures were approved by the Animal Use and Care Committee at the Johns Hopkins University School of Medicine. Timed pregnant CD-1 outbred mice (Charles River Laboratories, Wilmington, MA) were used in this study. Intrauterine injury was performed on embryonic day 17 (E17, full gestation is 19 days) according to an established animal protocol [45,46]. Briefly, mice were placed under isoflurane anesthesia and a mini-laparotomy was performed in the lower abdomen. LPS (Sigma,
Results
The glucoCEST effect in the placenta is shown in the S1 and S0 images in Fig. 1C. The dynamic changes of ΔSN in each individual placenta over a period of 25 min are shown in Fig. 2. In the PBS-exposed control group (Fig. 2A), it was observed that ΔSN dropped briefly between 1 and 3 min after the bolus of glucose infusion, attributed to the increase of bulk water through perfusion. ΔSN subsequently increased above the baseline for the rest of experiment, likely due to the enhanced glucoCEST
Discussion
We reported DGE MRI of normal and injured placentae using the glucoCEST technique. The dynamics of glucoCEST signal change after d-glucose infusion presumably reflect glucose uptake and transfer in the placenta. glucoCEST effects has been investigated previously in the brain, where increased glucoCEST contrast in tumors was found to relate to increased vascularity and blood-brain barrier break down [39,42]. In our in utero study, we found significantly reduced contrast in the injured placentae
Acknowledgement
This work is made possible by the following research supports: R21 NS098018, R01NS107417, K08 HD073315, DOD CDMRP AZ170028, and RO1EB019934.
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