ABSTRACT Objective Fontan circulation is characterized by chronically elevated central venous pressure (CVP) and reduced cardiac output, which may adversely affect the systemic microcirculation. We investigated whether Fontan circulation is associated with alterations of the endothelial glycocalyx. Methods Forty‐four patients with congenital heart disease undergoing postoperative endothelial glycocalyx evaluation were included. The perfused boundary region (PBR), an inverse indicator of glycocalyx dimensions, was measured noninvasively using GlycoCheck. PBR was compared between patients with Fontan and biventricular circulation, and its relationship with CVP was evaluated. Results Fourteen patients had Fontan circulation, including three with bidirectional Glenn circulation, and 30 had biventricular circulation. PBR was significantly higher in patients with Fontan circulation than in those with biventricular circulation (2.07 ± 0.15 vs. 1.72 ± 0.17 μm, p < 0.0001). CVP was also significantly higher in the Fontan group (13.0 ± 2.2 vs. 7.1 ± 2.8 mmHg, p < 0.0001). PBR was positively correlated with CVP ( r = 0.58, p < 0.0001). Conclusions Fontan circulation is associated with an increased PBR, suggesting alterations of the endothelial glycocalyx. The association between PBR and CVP suggests that chronic venous hypertension may be associated with systemic microcirculatory alterations in Fontan circulation.
ABSTRACT Objective The objective of this study was to develop 3D computational, tissue mimic models incorporating physiologically relevant microvascular network patterns for computing local alpha‐particle dosimetry and to explore the impact of network variability. Methods To obtain relevant microvascular network patterns, adult rat mesenteric tissues labeled for PECAM and Lyve‐1 were imaged. Images were used to create 3D polygon mesh models which were then tetrahedralized with delineated material properties. The models were subsequently incorporated into a Monte Carlo‐based radiation transport code and absorbed fractions—defined as the fraction of particle energy emitted from a source region that is deposited within a target region—were computed for the blood microvessels, lymphatic microvessels, and interstitial parenchyma tissue regions. Results A data set of absorbed fractions for alpha particles and electrons in each of the regions in the eight generated models acting as sources and targets was generated, noting the differences from previously used models that rely on a homogenization of both tissue and blood. Absorbed fractions approached the volume fraction of the target region with increasing energy source particle as expected. Variations in absorbed fractions up to 30% were observed between models. Conclusions Our results provide the first estimates of alpha particle and electron absorbed fractions associated with experimentally derived blood and lymphatic microvascular structures. The work suggests the importance of considering microvascular density, vessel diameters, and spatial location for tissue dosimetry in radiopharmaceutical therapy.
ABSTRACT The blood–brain barrier [BBB] is a highly specialized structure that regulates the influx and efflux of nutrients and metabolic waste to maintain homeostasis of the central nervous system. This selective permeability of the BBB is sustained by tight junctions that are supported by pericytes and astrocytes. Recently, extracellular vesicles have emerged as mediators of intercellular communication across and within the BBB. This review examines the bidirectional transport of EVs across the BBB and the distinct functional impacts of blood‐borne EVs. On the luminal side, circulating EVs derived from platelets, erythrocytes, and leukocytes convey systemic signals to the neurovasculature. Platelet‐derived EVs deliver growth factors and lipid mediators that promote vascular repair and modulate adaptive immunity during endothelial disruption. Erythrocyte‐derived EVs selectively shed surface markers like CD47 to regulate cellular turnover while simultaneously providing phosphatidylserine that maintains hemostasis and nitric oxide bioavailability. Meanwhile, leukocytic‐derived EVs protect and transport immunological cargo, such as MHC complexes and cytokines, functioning as critical sensors and amplifiers of immune surveillance at the vascular interface. Together, these circulating EV populations influence endothelial signaling, transporter expression, and tight junction integrity from the vascular side. Conversely, on the abluminal side, the roles of brain parenchymal‐derived EVs secreted by astrocytes, pericytes, neurons, and microglia are explored in regulating local neurovascular coupling, vascular tone, and endothelial responsiveness. Within this microenvironment, astrocyte‐derived EVs provide neurotrophic and neuroprotective support by delivering angiogenic factors and cytoprotective chaperone proteins like HSP70 to protect cells from mechanical and oxidative stress. Pericyte‐derived EVs preserve microvascular barrier integrity by transporting regulatory microRNAs and angiopoietin‐1 to directly upregulate endothelial tight junction proteins. Furthermore, neuron‐derived EVs participate in activity‐dependent signaling, transferring vital microRNAs to endothelial cells to promote vascular stability and support synaptic plasticity. By framing the BBB as an active communication system, this review underscores how peripheral and central EVs integrate systemic and neural environments, highlighting their fundamental roles in BBB physiology and, beyond, their profound implications as biomarkers of CNS distress and programmable vehicles for targeted drug delivery.
ABSTRACT Objective Explore potential associations between sublingual microcirculatory measures and plasma plasminogen activator inhibitor‐one concentrations in patients attending the kidney transplant assessment clinic and healthy controls. Methods A single‐center cohort study was performed by retrospectively recruiting 44 kidney transplant assessment clinic attendees and 15 nested non‐renal failure controls who were selected from a larger pool ( N = 44). The nested controls were frequency matched to the kidney transplant assessment clinic cohort by sex, ethnicity and diabetes. Sidestream dark field videomicroscopy (MicroScan, Microvision Medical, Amsterdam) of the sublingual microcirculation allowed quantification of five microcirculatory parameters in all patients: total vessel density, microvascular flow index, portion of perfused vessels, heterogeneity index and perfused vessel density. Plasma plasminogen activator inhibitor‐one concentrations were determined using sandwich ELISA. Median (IQR) were reported for non‐normally distributed data. Mann–Whitney‐Wilcoxon tests were performed to compare the distribution of ranks between non‐normally distributed groups ( U ‐statistic) with p < 0.05 considered statistically significant. The Benjamini–Hochberg adjustment was applied to nominal p ‐values ( q ‐value) to account for inflation of the false discovery rate across multiple exploratory analyses, with q < 0.05 considered statistically significant. Results Plasminogen activator inhibitor‐one levels were significantly higher in controls than those attending the transplant clinic (18.0 (11.5), 10.2 (6.8) ng/mL; U = 158, p = 0.006). Among kidney transplant patients, nominal associations revealed PAI‐1 was inversely correlated with hemodynamic parameters perfused vessel density ( p = 0.04, r = −0.32) and microvascular flow index ( p = 0.01, r = −0.38); neither survived the Benjamini–Hochberg adjustment ( q = 0.24 and q = 0.12, respectively). No other correlations between PAI‐1 and any of the sublingual microcirculatory measures survived the Benjamini–Hochberg adjustment in both cohorts. Conclusion PAI‐1 is potentially associated with maladaptive hemodynamic changes in the sublingual microcirculation, implying its dysregulation may potentiate microvascular dysfunction. The results, however, must be interpreted with caution as no associations survived the Benjamini–Hochberg correction.
ABSTRACT Objective Reconstruction of vascular topology from imperfect 3D imaging data is essential for accurate hemodynamic simulations. Therefore, we developed a “gap‐filling” method predicated on vascular biology and empirical patterns to restore incomplete vessels, independent of the imaging modality and spatial resolution employed. Methods Our gap‐filling algorithm reconstructs a vascular network based on distributions of its extant morphological features and employs different rules for healthy and tumor tissue. Algorithm performance was evaluated on (i) incomplete synthetic vascular trees with simulated CT noise, (ii) micro‐CT‐acquired brain tumor vasculature, (iii) micro‐MRI‐derived vasculature from a healthy mouse brain, and (iv) vasculature from the murine hippocampus imaged with light‐sheet microscopy (LSM). Results For synthetic vascular trees, our algorithm restored more gaps when the volume fraction was between 80% and 95%. Peak vessel segment recovery occurred for intermediate volume fractions (86%–89%). Gap‐filling performance was impacted when image noise was introduced. Across CT, MRI, and LSM, our method successfully reconnected missing vessel segments while preserving the overall features of the vascular network. Gap‐filling of tumor vasculature, with its abnormal topology, was better when tumor‐specific reconstruction rules were employed. Conclusions Our method showed efficient restoration of vascular network connectivity for 3D data derived from common imaging modalities at different resolutions. We also demonstrated the significance of applying distinct biologically‐informed rules when reconstructing healthy and tumor vascular networks.
