Placental Hypoxia Biomarkers in Placental Insufficiency Syndromes: Comparison
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Please note this is a comparison between Version 1 by Fatimah Al Darwish and Version 2 by Peter Tang.

Placental hypoxia poses significant risks to both the developing fetus and the mother during pregnancy, underscoring the importance of early detection and monitoring. Effectively identifying placental hypoxia and evaluating the deterioration in placental function requires reliable biomarkers. Molecular biomarkers in placental tissue can only be determined post-delivery and while maternal blood biomarkers can be measured over time, they can merely serve as proxies for placental function. Therefore, there is an increasing demand for non-invasive imaging techniques capable of directly assessing the placental condition over time. Advancements in imaging technologies, including photoacoustic and magnetic resonance imaging, offer promising tools for detecting and monitoring placental hypoxia. Integrating molecular and imaging biomarkers may revolutionize the detection and monitoring of placental hypoxia, improving pregnancy outcomes and reducing long-term health complications. 

  • placental hypoxia
  • molecular biomarkers
  • non-invasive imaging

1. Introduction

Placental insufficiency is associated with pregnancy complications, including pre-eclampsia (PE), fetal growth restriction (FGR), and stillbirth [1]. The pathophysiology of placental insufficiency is not entirely clear. It involves many factors, including anti-angiogenic [2][3], pro-inflammatory [4][5], and hypoxic factors [6], representing a complex web of interactions that profoundly affects the delicate balance required for optimal fetal development (Figure 1).
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Figure 1. Interplay of factors contributing to placental insufficiency: Examples of potential biomarkers related to each factor presented in the blue box. sFlt-1: Soluble fms-like tyrosine kinase-1, VEGF: Vascular endothelial growth factor, sEng: Soluble endoglin, PIGF: Placental growth factor, HIF-α: Hypoxia-inducible factor–alpha, CAIX: Carbonic Anhydrase IX, miR-210: microRNA-210, IL6: Interleukin 6, IL8: Interleukin 8, TNF-α: Tumor necrosis factor-alpha, G-CSF: Granulocyte colony-stimulating factor. (Created with BioRender.com) 
Placental hypoxia is a central factor in the development of placental insufficiency [7]. During placentation, the trophoblast cells differentiate and invade the maternal tissues, establishing the vital placental vascular network that facilitates nutrient and gas exchange between the mother and fetus. Any disruption in this process can lead to inadequate oxygen supply to the placenta and subsequently contribute to placental insufficiency and related pregnancy complications [1][7]. Therefore, assessing placental oxygenation or hypoxia is essential for understanding part of the pathophysiology of placental insufficiency.
The current approach to monitoring placental function involves ultrasound biometry, Doppler measurements, and cardiotocography to assess fetal wellbeing [8]. Despite their utility, the current biomarkers fall short in detecting early signs of placental insufficiency and precisely predicting adverse pregnancy outcomes. Approximately half of FGR cases remain undetected during pregnancy, leading to missed opportunities for timely interventions. Furthermore, once FGR is detected, existing monitoring strategies may inadequately identify fetal compromise in a timely and reliable manner [9]. Therefore, the incorporation of reliable biomarkers becomes imperative, especially in determining the optimal timing for intervention and delivery, a crucial consideration given the delicate balance between the risks of stillbirth and those associated with preterm birth [10].
One way to identify placental hypoxia is the use of molecular biomarkers, which can be detected in maternal blood during pregnancy or in placental tissue after delivery. Circulating biomarkers in maternal blood can provide valuable information about the overall health status. On the other hand, ex vivo investigations of placental tissue can be more specific, as it allows the direct examination of the placenta; however, it provides only a static representation of placental function at a specific time, disregarding the dynamic changes in placental development throughout gestation. Nevertheless, the assessment of the placenta after delivery becomes apparent too late to intervene, underscoring the importance of alternative methods to monitor placental health in real-time.
The assessment of dynamic changes of the in utero condition can be facilitated by non-invasive imaging techniques that can safely and effectively assess the placental and fetal condition over time. Non-invasive imaging offers a more comprehensive understanding of the underlying biological processes that drive placental disease development and progression during multiple gestational phases. Fortunately, recent advances in imaging technologies such as photoacoustic imaging (PAI) and magnetic resonance imaging (MRI) have shown great promise in detecting and monitoring placental hypoxia [11][12]. These imaging techniques have the potential to complement molecular biomarkers, offering a more thorough understanding of placental function throughout gestation.

2. Molecular Biomarkers of Hypoxia

Molecular biomarkers of hypoxia are proteins and genes that are activated in response to reduced oxygen levels. Several molecular biomarkers, including HIF-1α, CAIX, and miR-210, are involved in the cellular response to hypoxia [13][14][15]. These biomarkers can be measured in placental tissues or maternal blood samples using various techniques, such as immunohistochemistry, ELISA, and qPCR. Elevated levels of these biomarkers have been associated with placental hypoxia and adverse pregnancy outcomes. It is important to note that there are additional downstream biomarkers, particularly angiogenic factors, that provide further insight into vascular and endothelial dysfunction [2]. 

2.1. Hypoxia Inducible Factor (HIF)-α

Hypoxia Inducible Factor (HIF)-α is a transcription factor that plays a critical role in the cellular response to hypoxia or low oxygen levels. It regulates the expression of genes involved in various physiological processes, including angiogenesis, metabolism, and cell survival [16]. HIF is composed of two subunits: HIF-α and HIF-β. The HIF-α subunit is highly regulated by oxygen availability and it degrades rapidly under normoxia, while it stabilizes under hypoxia. Under hypoxic conditions, the stabilization of HIF-α results in its accumulation. Subsequently, HIF-α binds with HIF-β to form an active HIF complex, which triggers the transcription of target genes, including VEGF. This process aims to enhance the delivery of oxygen to the hypoxic region of tissues [1]. To gain insights into the significance of HIF-α in placental insufficiency, several studies have explored its expression and activity in both human and animal models.

2.2. Carbonic Anhydrase IX (CAIX)

Carbonic Anhydrase IX (CAIX) is a transmembrane protein that belongs to the carbonic anhydrase family and plays a crucial role in the regulation of acid-base balance in cells and highly expressed in hypoxic conditions [17]. In normal condition, CAIX is expressed in various tissues, including the gastrointestinal tract, kidney, and reproductive organs. In the placenta, CIAX expression can be observed in the villous cytotrophoblast during early gestation, indicating its involvement in the placental structure and function at this stage. Additionally, CIAX is consistently present in the chorionic plate mesenchymal cells throughout the entirety of a healthy gestation [18]. In placental insufficiency, CAIX have primarily been investigated in clinical research studies.

2.3. miR-210

MicroRNAs (miRNAs) are a type of small non-coding RNA that play a critical role in regulating gene expression at a posttranscriptional level and they function as a regulator of cell activities including growth, differentiation and apoptosis. Thus, they can serve as molecular biomarkers for various pathological conditions. Among the many miRNAs identified, miR-210 has emerged as a promising hypoxia biomarker in many diseases including cardiovascular diseases, cancer and PE hypoxia [19][20]. Overexpression of miR-210 appears to negatively impact cell migration and trophoblast invasion, which are crucial for normal placental development [20].

3. Imaging Biomarkers of Hypoxia

Imaging biomarkers are quantitative or qualitative measurements or features derived from images that provide information about biological processes or functions of a tissue or organ. These biomarkers can be used to assess disease progression, monitor treatment response, and aid in diagnosis. In pregnancy, direct and dynamic measures of placental function are possible through non-invasive imaging techniques such as MRI and photoacoustic imaging (PAI) [11][12].

3.1. T2* MRI

MRI has emerged as a non-invasive tool to assess placental function in vivo. Among various MRI sequences, T2* weighted MRI has shown promising results as an imaging biomarker of placental hypoxia [21]. T2* is a magnetic resonance imaging parameter that reflects the decay of the MRI signal intensity over time due to factors such as magnetic field inhomogeneities caused by the presence of substances like deoxygenated hemoglobin in the tissue [22]. This sensitivity to changes in the local magnetic field makes T2* MRI useful as an indicator of tissue hypoxia. Changes in T2* values can provide valuable insights into alterations in oxygenation levels within the tissue, making it a critical imaging biomarker for studying conditions like placental hypoxia. Baseline quantitative T2* values can be directly related to the oxygenation status of the tissue. Based on T2* MRI, two functional parameters have been used to assess the change in signal intensity in response to a gas challenge, such as hyperoxia or hypercapnia. One is delta T2*, which is based on quantitative T2* values, and this parameter estimates the change in placenta T2* value from two T2* scans obtained at different conditions. The other parameter is Blood Oxygen Level Dependent (BOLD) MRI, which is a relative measure of T2* signal change over time in response to a challenge. Delta T2* and delta BOLD under gas challenge reflects the hemodynamic status of the tissue.

3.2. Photoacoustic Imaging (PAI)

PAI is a novel imaging technique that combines optical and ultrasound imaging using non-ionizing nanosecond pulses [23]. This technique can measure placental oxygenation directly as oxyhemoglobin and deoxyhemoglobin absorb light at different wavelengths. With this information, it becomes possible to calculate the oxygen saturation levels and makes. PAI is a promising technique for placental insufficiency particularly due to its ability to provide absolute measurements of placental oxygenation, which allows for objective tracking of trends in oxygenation throughout gestation. However, its use in humans is hampered by the imaging depth limit, which is, however, an area of ongoing development [23]. Therefore, the application of PAI in pregnancy research is currently limited to animals.  

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