Non-Invasive Monitoring of Microvascular Oxygenation and Reactive Hyperemia using Hybrid, Near-Infrared Diffuse Optical Spectroscopy for Critical Care.

The detection of levels of impairment in microvascular oxygen consumption and reactive hyperemia is vital in critical care. However, there are no practical means for a robust and quantitative evaluation. This paper describes a protocol to evaluate these impairments using a hybrid near-infrared diffuse optical device. The device contains modules for near-infrared time-resolved and diffuse correlation spectroscopies and pulse-oximetry. These modules allow the non-invasive, continuous, and real-time measurement of the absolute, microvascular blood/tissue oxygen saturation (StO2) and the blood flow index (BFI) along with the peripheral arterial oxygen saturation (SpO2). This device uses an integrated, computer-controlled tourniquet system to execute a standardized protocol with optical data acquisition from the brachioradialis muscle. The standardized vascular occlusion test (VOT) takes care of the variations in the occlusion duration and pressure reported in the literature, while the automation minimizes inter-operator differences. The protocol we describe focuses on a 3-min occlusion period but the details described in this paper can readily be adapted to other durations and cuff pressures, as well as other muscles. The inclusion of an extended baseline and post-occlusion recovery period measurement allows the quantification of the baseline values for all the parameters and the blood/tissue deoxygenation rate that corresponds to the metabolic rate of oxygen consumption. Once the cuff is released, we characterize the tissue reoxygenation rate, magnitude, and duration of the hyperemic response in BFI and StO2. These latter parameters correspond to the quantification of the reactive hyperemia, which provides information about the endothelial function. Furthermore, the above-mentioned measurements of the absolute concentration of oxygenated and deoxygenated hemoglobin, BFI, the derived metabolic rate of oxygen consumption, StO2, and SpO2 provide a yet-to-be-explored rich data set that can exhibit disease severity, personalized therapeutics, and management interventions.

Transcriptomic and spatial dissection of human ex vivo right atrial tissue reveals proinflammatory microvascular changes in ischemic heart disease.

Cardiovascular disease plays a central role in the electrical and structural remodeling of the right atrium, predisposing to arrhythmias, heart failure, and sudden death. Here, we dissect with single-nuclei RNA sequencing (snRNA-seq) and spatial transcriptomics the gene expression changes in the human ex vivo right atrial tissue and pericardial fluid in ischemic heart disease, myocardial infarction, and ischemic and non-ischemic heart failure using asymptomatic patients with valvular disease who undergo preventive surgery as the control group. We reveal substantial differences in disease-associated gene expression in all cell types, collectively suggesting inflammatory microvascular dysfunction and changes in the right atrial tissue composition as the valvular and vascular diseases progress into heart failure. The data collectively suggest that investigation of human cardiovascular disease should expand to all functionally important parts of the heart, which may help us to identify mechanisms promoting more severe types of the disease.

Clinical Outcomes Associated With Various Microvascular Injury Patterns Identified by CMR After STEMI.

BACKGROUND: The prognostic significance of various microvascular injury (MVI) patterns after ST-segment elevation myocardial infarction (STEMI) is not well known. OBJECTIVES: This study sought to investigate the prognostic implications of different MVI patterns in STEMI patients. METHODS: The authors analyzed 1,109 STEMI patients included in 3 prospective studies. Cardiac magnetic resonance (CMR) was performed 3 days (Q1-Q3: 2-5 days) after percutaneous coronary intervention (PCI) and included late gadolinium enhancement imaging for microvascular obstruction (MVO) and T2∗ mapping for intramyocardial hemorrhage (IMH). Patients were categorized into those without MVI (MVO-/IMH-), those with MVO but no IMH (MVO+/IMH-), and those with IMH (IMH+). RESULTS: MVI occurred in 633 (57%) patients, of whom 274 (25%) had an MVO+/IMH- pattern and 359 (32%) had an IMH+ pattern. Infarct size was larger and ejection fraction lower in IMH+ than in MVO+/IMH- and MVO-/IMH- (infarct size: 27% vs 19% vs 18% [P < 0.001]; ejection fraction: 45% vs 50% vs 54% [P < 0.001]). During a median follow-up of 12 months (Q1-Q3: 12-35 months), a clinical outcome event occurred more frequently in IMH+ than in MVO+/IMH- and MVO-/IMH- subgroups (19.5% vs 3.6% vs 4.4%; P < 0.001). IMH+ was the sole independent MVI parameter predicting major adverse cardiovascular events (HR: 3.88; 95% CI: 1.93-7.80; P < 0.001). CONCLUSIONS: MVI is associated with future adverse outcomes only in patients with a hemorrhagic phenotype (IMH+). Patients with only MVO (MVO+/IMH-) had a prognosis similar to patients without MVI (MVO-/IMH-). This highlights the independent prognostic importance of IMH in assessing and managing risk after STEMI.

Use superb microvascular imaging to diagnose and predict metastatic cervical lymph nodes in patients with papillary thyroid carcinoma.

PURPOSE: Papillary thyroid carcinoma (PTC) with metastatic lymph nodes (LNs) is closely associated with disease recurrence. This study accessed the value of superb microvascular imaging (SMI) in the diagnosis and prediction of metastatic cervical LNs in patients with PTC. METHODS: A total of 183 cervical LNs (103 metastatic and 80 reactive) from 116 patients with PTC were analysed. Metastatic cervical LNs were confirmed by pathology or/and cytology; reactive cervical LNs were confirmed by pathology or clinical features. The characteristic of conventional ultrasound (US) was extracted using univariate and multivariate analyses. The diagnostic performance of US and SMI were compared using the area under the receiver operating curve (AUC) with corresponding sensitivity and specificity. A nomogram was developed to predict metastatic LNs in patients with PTC, based on multivariate analyses. RESULTS: L/S < 2, ill-defined border, absence of hilum, isoechoic or hyperechoic, heterogeneous internal echo, peripheral or mixed vascular pattern on color Doppler flow imaging (CDFI) and SMI, and a larger SMI vascular index appeared more frequently in metastatic LNs in the training datasets than in reactive LNs (P < 0.05). The diagnostic sensitivity, specificity and accuracy of SMI vs US are 94.4% and 87.3%, 79.3% and 69.3%, and 87.6% and 79.1%, respectively; SMI combined with US exhibited a higher AUC [0.926 (0.877-0.975)] than US only [0.829 (0.759-0.900)]. L/S < 2, peripheral or mixed vascular type on CDFI, and peripheral or mixed vascular types on SMI were independent predictors of metastatic LNs with PTC. The nomogram based on these three parameters exhibited excellent discrimination, with an AUC of 0.926. CONCLUSION: SMI was superior to US in diagnosing metastatic LNs in PTC. US combined with SMI significantly improved the diagnostic accuracy of metastatic cervical LNs with PTC. SMI is efficacious for differentiating and predicting metastatic cervical LNs.

Predictive nomograms based on gamma-glutamyl transpeptidase to prealbumin ratio for prognosis of hepatocellular carcinoma patients without microvascular invasion.

BACKGROUND: Hepatocellular carcinoma (HCC) presents a significant threat to individuals and healthcare systems due to its high recurrence rate. Accurate prognostic models are essential for improving patient outcomes. Gamma-glutamyl transpeptidase (GGT) and prealbumin (PA) are biomarkers closely related to HCC. This study aimed to investigate the predictive value of the GGT to PA ratio (GPR) and to construct prognostic nomograms for HCC patients without microvascular invasion. METHODS: We retrospectively analyzed data from 355 HCC patients who underwent radical hepatectomy at Shengjing Hospital of China Medical University between December 2012 and January 2021. Patients were randomly assigned to a training cohort (n = 267) and a validation cohort (n = 88). The linearity of GPR was assessed using restricted cubic spline (RCS) analysis, and the optimal cut-off value was determined by X-tile. Kaplan-Meier survival curves and log-rank tests were used to investigate the associations between GPR and both progression-free survival (PFS) and overall survival (OS). Cox multivariate regression analysis identified independent risk factors, enabling the construction of nomograms. Time-dependent receiver operating characteristic (ROC) and calibration curves were used to evaluate the accuracy of the nomograms. Decision curve analysis (DCA) assessed the predictive value of the models. RESULTS: Patients were categorized into GPR-low and GPR-high groups based on a GPR value of 333.33. Significant differences in PFS and OS were observed between the two groups (both P < 0.001). Cox multivariate analysis identified GPR as an independent risk factor for both PFS (OR = 1.80, 95% CI: 1.24-2.60, P = 0.002) and OS (OR = 1.87, 95% CI: 1.07-3.26, P = 0.029). The nomograms demonstrated good predictive performance, with C-index values of 0.69 for PFS and 0.76 for OS. Time-dependent ROC curves and calibration curves revealed the accuracy of the models in both the training and validation cohorts, with DCA results indicating notable clinical value. CONCLUSIONS: GPR emerged as an independent risk factor for both OS and PFS in HCC patients without microvascular invasion. The nomograms based on GPR demonstrated relatively robust predictive efficiency for prognosis.

Comparison of Doppler Imaging and Microvascular Imaging in Cervical Lymph Node Blood Flow Analysis.

Cervical lymph node metastasis is an important determinant of cancer stage and the selection of an appropriate treatment plan for patients with head and neck cancer. Therefore, metastatic cervical lymph nodes should be effectively differentiated from lymphoma, tuberculous lymphadenitis, and other benign lymphadenopathies. The aim of this work is to describe the performance of Doppler ultrasound and superb microvascular imaging (SMI) in evaluating blood flow information of cervical lymph nodes. In addition, the features of flow imaging in metastatic lymph nodes, lymphoma, and tuberculous lymphadenitis were described. Compared with Doppler ultrasound, SMI, the latest blood flow imaging technology, could detect more blood flow signals because the sensitivity, specificity, and accuracy of SMI in the diagnosis of cervical lymph node disease were higher. This article summarizes the value of Doppler ultrasound and SMI in evaluating cervical lymph node diseases and focuses on the diagnostic performance of SMI.

Association between retinal microvascular abnormalities and late-life brain amyloid-ß deposition: the ARIC-PET study.

BACKGROUND: Retinal microvascular signs are accessible measures of early alterations in microvascular dysregulation and have been associated with dementia; it is unclear if they are associated with AD (Alzheimer's disease) pathogenesis as a potential mechanistic link. This study aimed to test the association of retinal microvascular abnormalities in mid and late life and late life cerebral amyloid. METHODS: Participants from the ARIC-PET (Atherosclerosis Risk in Communities-Positron Emission Tomography) study with a valid retinal measure (N = 285) were included. The associations of mid- and late-life retinal signs with late-life amyloid-ß (Aß) by florbetapir PET were tested. Two different measures of Aß burden were included: (1) elevated amyloid (SUVR > 1.2) and (2) continuous amyloid SUVR. The retinal measures' association with Aß burden was assessed using logistic and robust linear regression models. A newly created retinal score, incorporating multiple markers of retinal abnormalities, was also evaluated in association with greater Aß burden. RESULTS: Retinopathy in midlife (OR (95% CI) = 0.36 (0.08, 1.40)) was not significantly associated with elevated amyloid burden. In late life, retinopathy was associated with increased continuous amyloid standardized value uptake ratio (SUVR) (ß (95%CI) = 0.16 (0.02, 0.32)) but not elevated amyloid burden (OR (95%CI) = 2.37 (0.66, 9.88)) when accounting for demographic, genetic and clinical risk factors. A high retinal score in late life, indicating a higher burden of retinal abnormalities, was also significantly associated with increased continuous amyloid SUVR (ß (95% CI) = 0.16 (0.04, 0.32)) independent of vascular risk factors. CONCLUSIONS: Retinopathy in late life may be an easily obtainable marker to help evaluate the mechanistic vascular pathway between retinal measures and dementia, perhaps acting via AD pathogenesis. Well-powered future studies with a greater number of retinal features and other microvascular signs are needed to test these findings.

Revealing the complexity of meniscus microvasculature through 3D visualization and analysis.

Three-dimensional information is essential for a proper understanding of the healing potential of the menisci and their overall role in the knee joint. However, to date, the study of meniscal vascularity has relied primarily on two-dimensional imaging techniques. Here we present a method to elucidate the intricate 3D meniscal vascular network, revealing its spatial arrangement, connectivity and density. A polymerizing contrast agent was injected into the femoral artery of human cadaver legs, and the meniscal microvasculature was examined using micro-computed tomography at different levels of detail and resolution. The 3D vascular network was quantitatively assessed in a zone-base analysis using parameters such as diameter, length, tortuosity, and branching patterns. The results of this study revealed distinct vascular patterns within the meniscus, with the highest vascular volume found in the outer perimeniscal zone. Variations in vascular parameters were found between the different circumferential and radial meniscal zones. Moreover, through state-of-the-art 3D visualization using micro-CT, this study highlighted the importance of spatial resolution in accurately characterizing the vascular network. These findings, both from this study and from future research using this technique, improve our understanding of microvascular distribution, which may lead to improved therapeutic strategies.

AngioMT: A MATLAB based 2D image-to-physics tool to predict oxygen transport in vascularized microphysiological systems.

Microphysiological models (MPS) are increasingly getting recognized as in vitro preclinical systems of pathophysiology and drug discovery. However, there is also a growing need to adapt and advance MPS to include the physiological contributions of the capillary vascular dynamics, because they undergo angiogenesis or vasculogenesis to deliver soluble oxygen and nutrients to its organs. Currently, the process of formation of microvessels in MPS is measured arbitrarily, and vascularized MPS do not include oxygen measurements in their analysis. Sensing and measuring tissue oxygen delivery is extremely difficult because it requires access to opaque and deep tissue, and/or requires extensive integration of biosensors that makes such systems impractical to use in the real world. Here, a finite element method-based oxygen transport program, called AngioMT, is built in MATLAB. AngioMT processes the routinely acquired 2D confocal images of microvascular networks in vitro and solves physical equations of diffusion-reaction dominated oxygen transport phenomena. This user-friendly image-to-physics transition in AngioMT is an enabling tool of MPS analysis because unlike the averaged morphological measures of vessels, it provides information of the spatial transport of oxygen both within the microvessels and the surrounding tissue regions. Further, it solves the more complex higher order reaction mechanisms which also improve the physiological relevance of this tool when compared directly against in vivo measurements. Finally, the program is applied in a multicellular vascularized MPS by including the ability to define additional organ/tissue subtypes in complex co-cultured systems. Therefore, AngioMT serves as an analytical tool to enhance the predictive power and performance of MPS that incorporate microcirculation.

Semi-automated protocol to quantify and characterize fluorescent three-dimensional vascular images.

The microvasculature facilitates gas exchange, provides nutrients to cells, and regulates blood flow in response to stimuli. Vascular abnormalities are an indicator of pathology for various conditions, such as compromised vessel integrity in small vessel disease and angiogenesis in tumors. Traditional immunohistochemistry enables the visualization of tissue cross-sections containing exogenously labeled vasculature. Although this approach can be utilized to quantify vascular changes within small fields of view, it is not a practical way to study the vasculature on the scale of whole organs. Three-dimensional (3D) imaging presents a more appropriate method to visualize the vascular architecture in tissue. Here we describe the complete protocol that we use to characterize the vasculature of different organs in mice encompassing the methods to fluorescently label vessels, optically clear tissue, collect 3D vascular images, and quantify these vascular images with a semi-automated approach. To validate the automated segmentation of vascular images, one user manually segmented one hundred random regions of interest across different vascular images. The automated segmentation results had an average sensitivity of 83±11% and an average specificity of 91±6% when compared to manual segmentation. Applying this procedure of image analysis presents a method to reliably quantify and characterize vascular networks in a timely fashion. This procedure is also applicable to other methods of tissue clearing and vascular labels that generate 3D images of microvasculature.

An evaluation of the effects of localised skin cooling on microvascular, inflammatory, structural, and perceptual responses to sustained mechanical loading of the sacrum: A study protocol.

This study protocol aims to investigate how localised cooling influences the skin's microvascular, inflammatory, structural, and perceptual tolerance to sustained mechanical loading at the sacrum, evaluating factors such as morphology, physiology, and perceptual responses. The protocol will be tested on individuals of different age, sex, skin tone and clinical status, using a repeated-measure design with three participants cohorts: i) young healthy (n = 35); ii) older healthy (n = 35); iii) spinal cord injured (SCI, n = 35). Participants will complete three testing sessions during which their sacrum will be mechanically loaded (60 mmHg; 45 min) and unloaded (20 min) with a custom-built thermal probe, causing pressure-induced ischemia and post-occlusive reactive hyperaemia. Testing sessions will differ by the probe's temperature, which will be set to either 38°C (no cooling), 24°C (mild cooling), or 16°C (strong cooling). We will measure skin blood flow (via Laser Doppler Flowmetry; 40 Hz); pro- and anti-inflammatory biomarkers in skin sebum (Sebutape); structural skin properties (Optical Coherence Tomography); and ratings of thermal sensation, comfort, and acceptance (Likert Scales); throughout the loading and unloading phases. Changes in post-occlusive reactive hyperaemia will be considered as the primary outcome and data will be analysed for the independent and interactive effects of stimuli's temperature and of participant group on within- and between-subject mean differences (and 95% Confidence Intervals) in peak hyperaemia, by means of a 2-way mixed model ANOVA (or Friedman). Regression models will also be developed to assess the relationship between absolute cooling temperatures and peak hyperaemia. Secondary outcomes will be within- and between-subject mean changes in biomarkers' expression, skin structural and perceptual responses. This analysis will help identifying physiological and perceptual thresholds for the protective effects of cooling from mechanically induced damage underlying the development of pressure ulcers in individuals varying in age and clinical status.

Acod1/itaconate activates Nrf2 in pulmonary microvascular endothelial cells to protect against the obesity-induced pulmonary microvascular endotheliopathy.

BACKGROUND: Obesity is the main risk factor leading to the development of various respiratory diseases, such as asthma and pulmonary hypertension. Pulmonary microvascular endothelial cells (PMVECs) play a significant role in the development of lung diseases. Aconitate decarboxylase 1 (Acod1) mediates the production of itaconate, and Acod1/itaconate axis has been reported to play a protective role in multiple diseases. However, the roles of Acod1/itaconate axis in the PMVECs of obese mice are still unclear. METHODS: mRNA-seq was performed to identify the differentially expressed genes (DEGs) between high-fat diet (HFD)-induced PMVECs and chow-fed PMVECs in mice (|log2 fold change| ≥ 1, p ≤ 0.05). Free fatty acid (FFA) was used to induce cell injury, inflammation and mitochondrial oxidative stress in mouse PMVECs after transfection with the Acod1 overexpressed plasmid or 4-Octyl Itaconate (4-OI) administration. In addition, we investigated whether the nuclear factor erythroid 2-like 2 (Nrf2) pathway was involved in the effects of Acod1/itaconate in FFA-induced PMVECs. RESULTS: Down-regulated Acod1 was identified in HFD mouse PMVECs by mRNA-seq. Acod1 expression was also reduced in FFA-treated PMVECs. Acod1 overexpression inhibited cell injury, inflammation and mitochondrial oxidative stress induced by FFA in mouse PMVECs. 4-OI administration showed the consistent results in FFA-treated mouse PMVECs. Moreover, silencing Nrf2 reversed the effects of Acod1 overexpression and 4-OI administration in FFA-treated PMVECs, indicating that Nrf2 activation was required for the protective effects of Acod1/itaconate. CONCLUSION: Our results demonstrated that Acod1/Itaconate axis might protect mouse PMVECs from FFA-induced injury, inflammation and mitochondrial oxidative stress via activating Nrf2 pathway. It was meaningful for the treatment of obesity-caused pulmonary microvascular endotheliopathy.

Angiotensin II Directly Increases Endothelial Calcium and Nitric Oxide in Kidney and Brain Microvessels In Vivo With Reduced Efficacy in Hypertension.

BACKGROUND: The vasoconstrictor effects of angiotensin II via type 1 angiotensin II receptors in vascular smooth muscle cells are well established, but the direct effects of angiotensin II on vascular endothelial cells (VECs) in vivo and the mechanisms how VECs may mitigate angiotensin II-mediated vasoconstriction are not fully understood. The present study aimed to explore the molecular mechanisms and pathophysiological relevance of the direct actions of angiotensin II on VECs in kidney and brain microvessels in vivo. METHODS AND RESULTS: Changes in VEC intracellular calcium ([Ca2+]i) and nitric oxide (NO) production were visualized by intravital multiphoton microscopy of cadherin 5-Salsa6f mice or the endothelial uptake of NO-sensitive dye 4-amino-5-methylamino-2',7'-difluorofluorescein diacetate, respectively. Kidney fibrosis by unilateral ureteral obstruction and Ready-to-use adeno-associated virus expressing Mouse Renin 1 gene (Ren1-AAV) hypertension were used as disease models. Acute systemic angiotensin II injections triggered >4-fold increases in VEC [Ca2+]i in brain and kidney resistance arterioles and capillaries that were blocked by pretreatment with the type 1 angiotensin II receptor inhibitor losartan, but not by the type 2 angiotensin II receptor inhibitor PD123319. VEC responded to acute angiotensin II by increased NO production as indicated by >1.5-fold increase in 4-amino-5-methylamino-2',7'-difluorofluorescein diacetate fluorescence intensity. In mice with kidney fibrosis or hypertension, the angiotensin II-induced VEC [Ca2+]i and NO responses were significantly reduced, which was associated with more robust vasoconstrictions, VEC shedding, and microthrombi formation. CONCLUSIONS: The present study directly visualized angiotensin II-induced increases in VEC [Ca2+]i and NO production that serve to counterbalance agonist-induced vasoconstriction and maintain residual organ blood flow. These direct and endothelium-specific angiotensin II effects were blunted in disease conditions and linked to endothelial dysfunction and the development of vascular pathologies.

Neovascularization by DPSC-ECs in a Tube Model for Pulp Regeneration Study.

The process of neovascularization during cell-based pulp regeneration is difficult to study. Here we developed a tube model that simulates root canal space and allows direct visualization of the vascularization process in vitro. Endothelial-like cells (ECs) derived from guiding human dental pulp stem cells (DPSCs) into expressing endothelial cell markers CD144, vWF, VEGFR1, and VEGFR2 were used. Human microvascular endothelial cells (hMVECs) were used as a positive control. DPSC-ECs formed tubules on Matrigel similar to hMVECs. Cells were mixed in fibrinogen/thrombin or mouse blood and seeded into wells of 96-well plates or injected into a tapered plastic tube (14 mm in length and 1 or 2 mm diameter of the apex opening) with the larger end sealed with MTA to simulate root canal space. Cells/gels in wells or tubes were incubated for various times in vitro and observed under the microscope for morphological changes. Samples were then fixed and processed for histological analysis to determine vessel formation. Vessel-like networks were observed in culture from 1 to 3 d after cell seeding. Cells/gels in 96-well plates were maintained up to 25 d. Histologically, both hMVECs and DPSC-ECs in 96-well plates or tubes showed intracellular vacuole formation. Some cells showed merged large vacuoles indicating the lumenization. Tubular structures were also observed resembling blood vessels. Cells appeared healthy throughout the tube except some samples (1 mm apical diameter) in the coronal third. Histological analysis also showed pulp-like soft tissue throughout the tube samples with vascular-like structures. hMVECs formed larger vascular lumen size than DPSC-ECs while the latter tended to have more lumen and tubular structure counts. We conclude that DPSC-ECs can form vascular structures and sustained in the 3-dimensional fibrin gel system in vitro. The tube model appears to be a proper and simple system simulating the root canal space for vascular formation and pulp regeneration studies.

miR-4685-3p Alleviates Human Brain Microvascular Endothelial Cells Injury by Regulating MMP9.

OBJECTIVE: Cerebral microbleeds (CMBs) are punctate hemorrhagic lesions within the brain parenchyma and are a classic manifestation of cerebral small vessel disease (CSVD). The primary objective of this study is to investigate the potential role of miR-4685-3p and underlying mechanisms by which miR-4685-3p modulates matrix metalloproteinase-9 (MMP9) in cerebral microvascular endothelial cell injury. METHODS: We employed high-throughput sequencing to screen for differentially expressed miRNAs in the peripheral blood of patients with CMBs and healthy controls. Employing lipopolysaccharide (LPS) to induce cellular damage, we aim to establish a model of human brain microvascular endothelial cells (hCMEC/D3) injury. We also had cells transfected with miR-4685-3p mimic and MMP9 overexpression plasmid. We utilized quantitative polymerase chain reaction (qPCR) to assess the expression levels of miR-4685-3p and performed Western blot analysis to examine MMP9 expression levels in the cells. We employed the CCK-8 assay, TUNEL assay, and tube formation assay to evaluate cellular viability, apoptotic rates, and angiogenic capabilities. Furthermore, dual-luciferase reporter assay analysis was conducted to confirm the relationship between miR-4685-3p and MMP9. RESULTS: The sequencing results indicated a downregulation of miR-4685-3p in the peripheral blood of patients with CMBs. Within the context of LPS-induced injury to hCMEC/D3 cells, miR-4685-3p exhibits reduced expression, whereas MMP9 expression levels are elevated. The elevation of miR-4685-3p expression levels attenuates LPS-induced cellular apoptosis and enhances the viability and tube-forming capacity of hCMEC/D3 cells. Concomitant transfection with MMP9 overexpression constructs effectively reversed the detrimental effects of LPS on hCMEC/D3 cell integrity. We further confirmed that miR-4685-3p overexpression directly targets MMP9, leading to negative regulation of MMP9 expression. CONCLUSION: Upregulating miR-4685-3p, which targets the MMP9 axis, mitigated LPS-induced cerebral microvascular endothelial cell injury, potentially playing a protective role in the progression of CMBs.

Optical coherence tomography angiography for detection of microvascular changes in early diabetes: A systematic review and meta-analysis.

AIMS: To evaluate the effectiveness of optical coherence tomography angiography (OCTA) in detecting early intraocular microvascular changes in diabetic patients. MATERIALS AND METHODS: A systematic study search was performed on PubMed, Medline, Embase, and the Cochrane Library, ranging from January 2012 to March 2023. Controlled studies compared diabetes mellitus (DM) patients with non-diabetic retinopathy (NDR) or patients with mild non-proliferative diabetic retinopathy (mild NPDR) to healthy people. These studies included parameters of OCTA such as foveal avascular zone (FAZ), vessel density of superficial capillary plexus (VDscp), vessel density of deep capillary plexus (VDdcp), and peripapillary VD. The relevant effect model was used according to the heterogeneity, and the mean difference and 95% confidence intervals were calculated. RESULTS: A total of 18 studies with 2101 eyes were eventually included in this meta-analysis. Our results demonstrated that early alterations of VDscp, VDdcp, and peripapillary VD in NDR patients had a significant difference compared with healthy people by OCTA (VDscp: WMD = -1.34, 95% CI: -1.99 to -0.68, P < 0.0001. VDdcp: WMD = -2.00, 95% CI: -2.95 to -1.04, P < 0.0001. Peripapillary VD: WMD = -1.07, 95% CI: -1.70 to -0.43, P = 0.0010). However, there was no statistically significant difference in total FAZ between them (WMD = -0.00, 95% CI: -0.02-0.01, P = 0.84). In addition, for patients with mild NPDR, OCTA could illustrate prominent changes in VDscp, VDdcp, and total FAZ compared with healthy people (VDscp: WMD = -6.11, 95% CI: -9.90 to -2.32, P = 0.002. VDdcp: WMD = -4.26, 95% CI: -5.95 to -2.57, P < 0.00001. FAZ: WMD = 0.06, 95% CI: 0.01-0.11, P = 0.03). CONCLUSIONS: In diabetic patients with or without retinopathy, the parameters of OCTA such as VDscp, VDdcp, and peripapillary vessel density were demonstrated as potential biomarkers in monitoring the early alterations of retinal microangiopathy, while total FAZ may have no significant changes in diabetic patients without retinopathy.

Coronary Microvascular Function Following Severe Preeclampsia.

BACKGROUND: Preeclampsia is a pregnancy-specific hypertensive disorder associated with an imbalance in circulating proangiogenic and antiangiogenic proteins. Preclinical evidence implicates microvascular dysfunction as a potential mediator of preeclampsia-associated cardiovascular risk. METHODS: Women with singleton pregnancies complicated by severe antepartum-onset preeclampsia and a comparator group with normotensive deliveries underwent cardiac positron emission tomography within 4 weeks of delivery. A control group of premenopausal, nonpostpartum women was also included. Myocardial flow reserve, myocardial blood flow, and coronary vascular resistance were compared across groups. sFlt-1 (soluble fms-like tyrosine kinase receptor-1) and PlGF (placental growth factor) were measured at imaging. RESULTS: The primary cohort included 19 women with severe preeclampsia (imaged at a mean of 15.3 days postpartum), 5 with normotensive pregnancy (mean, 14.4 days postpartum), and 13 nonpostpartum female controls. Preeclampsia was associated with lower myocardial flow reserve (ß, -0.67 [95% CI, -1.21 to -0.13]; P=0.016), lower stress myocardial blood flow (ß, -0.68 [95% CI, -1.07 to -0.29] mL/min per g; P=0.001), and higher stress coronary vascular resistance (ß, +12.4 [95% CI, 6.0 to 18.7] mm Hg/mL per min/g; P=0.001) versus nonpostpartum controls. Myocardial flow reserve and coronary vascular resistance after normotensive pregnancy were intermediate between preeclamptic and nonpostpartum groups. Following preeclampsia, myocardial flow reserve was positively associated with time following delivery (P=0.008). The sFlt-1/PlGF ratio strongly correlated with rest myocardial blood flow (r=0.71; P<0.001), independent of hemodynamics. CONCLUSIONS: In this exploratory cross-sectional study, we observed reduced coronary microvascular function in the early postpartum period following preeclampsia, suggesting that systemic microvascular dysfunction in preeclampsia involves coronary microcirculation. Further research is needed to establish interventions to mitigate the risk of preeclampsia-associated cardiovascular disease.

Microvascular Perfusion Imaging in Alzheimer's Disease.

Alzheimer's disease (AD) is the leading cause of dementia worldwide and significantly impacts the essential functions of daily life and social activities. Research on AD has found that its pathogenesis is related to the extracellular accumulation of amyloid-beta (Aß) plaques and intracellular neurofibrillary tangles in the cortical and limbic areas of the human brain, as well as cerebrovascular factors. The detection of Aß or tau can be performed using various probes and methodologies. However, these modalities are expensive to implement and often require invasive procedures, limiting accessibility on a large scale. While magnetic resonance imaging (MRI) and computed tomography (CT) are generally used for morphological and structural brain imaging, they show wide variability in their accuracy for the clinical diagnosis of AD. Several novel imaging modalities have emerged as alternatives that can accurately and vividly display the changes in blood flow and metabolism in each brain area and enable physicians and researchers to gain insights into the generation and progression of the cerebro-microvascular pathologies of AD. In this review, we summarize the current knowledge on microvascular perfusion imaging modalities and their application in AD, including MRI (dynamic susceptibility contrast-MRI, arterial spin labeling-MRI), CT (cerebral CT perfusion imaging), emission computed tomography (positron emission tomography (PET), single-photon emission computed tomography (SPECT)), transcranial doppler ultrasonography (TCD), and retinal microvascular imaging (optical coherence tomography imaging, computer-assisted methods for evaluating retinal vasculature).

Research progress in the pathogenesis of hormone-induced femoral head necrosis based on microvessels: a systematic review.

Hormonal necrosis of the femoral head is caused by long-term use of glucocorticoids and other causes of abnormal bone metabolism, lipid metabolism imbalance and blood microcirculation disorders in the femoral head, resulting in bone trabecular fracture, bone tissue necrosis collapse, and hip dysfunction. It is the most common type of non-traumatic necrosis of the femoral head, and its pathogenesis is complex, while impaired blood circulation is considered to be the key to its occurrence. There are a large number of microvessels in the femoral head, among which H-type vessels play a decisive role in the "angiogenesis and osteogenesis coupling", and thus have an important impact on the occurrence and development of femoral head necrosis. Glucocorticoids can cause blood flow injury of the femoral head mainly through coagulation dysfunction, endothelial dysfunction and impaired angiogenesis. Glucocorticoids may inhibit the formation of H-type vessels by reducing the expression of HIF-1α, PDGF-BB, VGEF and other factors, thus causing damage to the "angiogenesis-osteogenesis coupling" and reducing the ability of necrosis reconstruction and repair of the femoral head. Leads to the occurrence of hormonal femoral head necrosis. Therefore, this paper reviewed the progress in the study of the mechanism of hormone-induced femoral head necrosis based on microvascular blood flow at home and abroad, hoping to provide new ideas for the study of the mechanism of femoral head necrosis and provide references for clinical treatment of femoral head necrosis.