Application of Dynamic Contrast Enhanced Magnetic Resonance Imaging to Evaluate Angiogenic Response and Vascular Permeability

Titration of the angiogenic response to stress is critical for controlling the sufficiency of oxygen delivery to organs during normal development and in response to disease. One of the best examples of this phenomenon is placental blood vessel and vascular network development, which must keep pace to satisfy the metabolic demands of the developing embryo. In addition to blood vessel number, there must be an adequate communication between the emerging blood vessels, endovascular trophoblasts, and the extracellular matrix and cells within the surrounding mesoderm.

In this study, Cohen et al¹ used a creative approach to interrogate the role of embryonic TGs (transglutaminases) produced by the vascular compartment (Figure). Their study specifically evaluated whether tissue TG2 and FXIII (factor XIII) modulate implantation site microvasculature permeability. TG2 and FXIIII are both expressed at the maternal-fetal interface during early embryonic development. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) was performed using a high field strength MRI machine equipped with a spectrometer. A linear coil was placed on the pregnant mice to acquire the images as described in prior reports.^2–4 T1 weighted images were acquired since they allow visualization of the gadolinium contrast. These images were acquired at various intervals after administration of contrast and taken with various parameters, such as change in contrast agent concentration in the region of interest over time. Fractional blood volume and permeability surface area product was also calculated. The authors found that there were significantly low permeability surface area product values, consistent with attenuated extravasation of the MRI contrast agent in the implantation site with trophoblast cells overexpressing FXIII but not overexpressing TG2 relative to the control group. In addition, fractional blood volume was reduced significantly at implantation site of embryos with trophoblast cells overexpressing either FXIII or TG2. This is a particularly interesting discovery because MRI enabled detection of the role of 2 TG isoenzymes, TG2 and FXIII, in decidual angiogenesis during early embryo implantation. The authors discuss that these changes may have implications in embryo implantation failure,⁵ preeclampsia and intrauterine growth restriction since these depend on early uterine blood supply structure development⁶ and impaired trophoblast invasion of the placental bed spiral arterioles in pregnancy.⁷

Figure. Graphical abstract on the study of TG2 and FXIII in decidual angiogenesis.

A, Cohen et al¹ apply an innovative strategy involving phage display–mediated identification of substrate analogs, Gd-labeling of the analogs, and DCE-MRI to reveal new roles of TG2 and FXIII in decidual angiogenesis. These studies are complemented by CRISPR-mediated gene deletion, lentiviral overexpression, and histological analyses. B, The study presented by Cohen et al¹ supports roles for TG2 and FXIII in both decidual vascular permeability and blood volume regulation following blastocyst attachment. Upper diagram: illustration of a subset of developmental events that occur in the uterus during implantation and early placentation. Lower images contain examples of the maternal-fetal interface at each developmental stage. Left: a blastocyst and adjacent ULE with trophectoderm in red, inner cell mass in green, and ULE in blue. Middle: the remodeling implantation site with decidua in green and ULE in red. Right: an implanted embryo with basal lamina in green, extraembryonic cells in white, and epiblast in red. DCE-MRI indicates dynamic contrast enhanced-MRI; De, decidua; ECM, extracellular matrix; Em, embryo; Gd, gadolinium; SA, substrate analogs; SpA, spiral arteries; and ULE, uterine luminal epithelium.

The imaging strategy used by Cohen et al¹ might be used for evaluation of TGs in angiogenesis in other tissues and pathologies as it is likely that these same developmental mechanisms are recruited to assist other organs to respond disease. Within the context of TG G-protein biology in the heart, TG2 may protect against ischemia/reperfusion injury through an adrenergic receptor-independent protective role that lowers preischemic values in heart rate, coronary flow, aortic flow, and aortic pressure when compared with control animals.⁸ DCE-MRI could be applied to TG2^−/− hearts, which are sensitive to ischemia/reperfusion injury. Similarly, FXIII-deficient mice show cardiac fibrosis that may be caused by a faulty or delayed reparative process initiated by abnormal hemorrhagic events within heart tissue.⁹ In the clinical setting, these vascular assessments are generally qualitative.¹⁰ For example, in the cerebrovascular field, gadolinium-based contrast has been used in clinical practice for various pathologies involving vascular permeability such as breakdown of the brain blood barrier, but potential toxicity should be carefully weighed against diagnostic benefit.^11,12

With respect to cardiovascular disease, DCE-MRI with quantitative physiological gadolinium-based contrast parameters has indeed been applied to evaluate carotid atherosclerosis and cardiac muscle perfusion.^13–15 A recent study by Wang et al¹⁶ has also suggested that DCE-MRI may help to evaluate ischemic heart disease, cardiac vascular sufficiency, and fibrosis. The development of DCE-MRI capable of imaging TG activities now raises the prospect of identifying the earliest stages of vascular insufficiency when treatment interventions could prevent the development of irreversible scar formation. Further investigation into new applications of DCE-MRI holds great promise to enhance our ability to quantify, or at least qualify, angiogenic response, vascular permeability, and vascular sufficiency in the study of organ-specific vascular development and disease.