Corneal endothelial density and morphology in long-term soft contact lens users in Japan: a retrospective cross-sectional study of 17,732 eyes.

PURPOSE: There is a lack of long-term and large-scale studies on the adverse effects of soft contact lenses (SCLs) on the corneal endothelia of Asian populations. Here, we aimed to examine the effects of long-term SCL use on corneal endothelial density and morphology. MATERIALS AND METHODS: This retrospective study involved consecutive patients at the Miyata Eye Hospital (Miyazaki, Japan), who had used SCLs for more than 1 year. Patients with ophthalmological disorders without refractive errors were excluded. The period of SCL use, SCL type, corneal endothelial cell density (ECD), appearance rate of hexagonal cells (HEX), and coefficient of variation of cells (CV) were analyzed. RESULTS: In total, 17,732 eyes of 8866 patients were included in the analysis (age, 26.0 ± 8.8 years). The mean period of SCL use was 6.3 ± 5.4 years. Multivariate regression analysis revealed that ECD and HEX were significantly negatively correlated with the period of SCL use, age, and sex (p < 0.001 for all). The CV was significantly positively correlated with the period of use (p < 0.001), sex (p = 0.002), and age (p < 0.001). CONCLUSIONS: Corneal ECD, HEX, and CV were significantly associated with the period of SCL use in long-term users. It is essential to regularly check the corneal endothelium in patients with a history of long-term SCL use.

LncRNA-SNHG16 Protects Against Oxidative Stress-Induced Vascular Endothelial Cell Injury in Cardiovascular Diseases by Regulating the miR-23a-3p-GLS-Glutamine Metabolism Axis.

Cardiovascular diseases are disorders of the heart and vascular system that cause high mortality rates worldwide. Vascular endothelial cell (VEC) injury caused by oxidative stress (OS) is an important event in the development of various cardiovascular diseases, including ischemic heart disease. This study aimed to investigate the critical roles and molecular mechanisms of long non-coding RNA (lncRNA) SNHG16 in regulating vascular endothelial cell injury under oxidative stress. We demonstrated that SNHG16 was significantly downregulated and miRNA-23a-3p was notably induced in human vascular endothelial cells under OS. Overexpressing SNHG16 or silencing miR-23a-3p effectively mitigated the OS-induced VEC injury. Additionally, glutamine metabolism of VECs was suppressed under OS. SNHG16 protected the OS-suppressed glutamine metabolism, while miR-23a-3p functioned oppositely in VECs. Furthermore, SNHG16 downregulated miR-23a-3p by sponging miR-23a-3p, which direct targeted the glutamine metabolism enzyme, GLS. Finally, restoring miR-23a-3p in SNHG16-overexpressing VECs successfully reversed the protective effect of SNHG16 on vascular endothelial cell injury under OS. In summary, our results revealed the roles and molecular mechanisms of the SNHG16-mediated protection against VEC injury under OS by modulating the miR-23a-3p-GLS pathway.

APP-CD74 axis mediates endothelial cell-macrophage communication to promote kidney injury and fibrosis.

Background: Kidney injuries often carry a grim prognosis, marked by fibrosis development, renal function loss, and macrophage involvement. Despite extensive research on macrophage polarization and its effects on other cells, like fibroblasts, limited attention has been paid to the influence of non-immune cells on macrophages. This study aims to address this gap by shedding light on the intricate dynamics and diversity of macrophages during renal injury and repair. Methods: During the initial research phase, the complexity of intercellular communication in the context of kidney injury was revealed using a publicly available single-cell RNA sequencing library of the unilateral ureteral obstruction (UUO) model. Subsequently, we confirmed our findings using an independent dataset from a renal ischemia-reperfusion injury (IRI) model. We treated two different types of endothelial cells with TGF-ß and co-cultured their supernatants with macrophages, establishing an endothelial cell and macrophage co-culture system. We also established a UUO and an IRI mouse model. Western blot analysis, flow cytometry, immunohistochemistry and immunofluorescence staining were used to validate our results at multiple levels. Results: Our analysis revealed significant changes in the heterogeneity of macrophage subsets during both injury processes. Amyloid ß precursor protein (APP)-CD74 axis mediated endothelial-macrophage intercellular communication plays a dominant role. In the in vitro co-culture system, TGF-ß triggers endothelial APP expression, which subsequently enhances CD74 expression in macrophages. Flow cytometry corroborated these findings. Additionally, APP and CD74 expression were significantly increased in the UUO and IRI mouse models. Immunofluorescence techniques demonstrated the co-localization of F4/80 and CD74 in vivo. Conclusion: Our study unravels a compelling molecular mechanism, elucidating how endothelium-mediated regulation shapes macrophage function during renal repair. The identified APP-CD74 signaling axis emerges as a promising target for optimizing renal recovery post-injury and preventing the progression of chronic kidney disease.

SCAR-6 elncRNA locus epigenetically regulates PROZ and modulates coagulation and vascular function.

In this study, we characterize a novel lncRNA-producing gene locus that we name Syntenic Cardiovascular Conserved Region-Associated lncRNA-6 (scar-6) and functionally validate its role in coagulation and cardiovascular function. A 12-bp deletion of the scar-6 locus in zebrafish (scar-6gib007Δ12/Δ12) results in cranial hemorrhage and vascular permeability. Overexpression, knockdown and rescue with the scar-6 lncRNA modulates hemostasis in zebrafish. Molecular investigation reveals that the scar-6 lncRNA acts as an enhancer lncRNA (elncRNA), and controls the expression of prozb, an inhibitor of factor Xa, through an enhancer element in the scar-6 locus. The scar-6 locus suppresses loop formation between prozb and scar-6 sequences, which might be facilitated by the methylation of CpG islands via the prdm14-PRC2 complex whose binding to the locus might be stabilized by the scar-6 elncRNA transcript. Binding of prdm14 to the scar-6 locus is impaired in scar-6gib007Δ12/Δ12 zebrafish. Finally, activation of the PAR2 receptor in scar-6gib007Δ12/Δ12 zebrafish triggers NF-κB-mediated endothelial cell activation, leading to vascular dysfunction and hemorrhage. We present evidence that the scar-6 locus plays a role in regulating the expression of the coagulation cascade gene prozb and maintains vascular homeostasis.

The neo-potential therapeutic strategy in preeclampsia: Downregulated miR-26a-2-3p motivates endothelial cell injury by targeting 15-LOX-1.

Preeclampsia (PE) poses a life-threatening risk for both mothers and babies, and its onset and progression are linked to endothelial injury. The enzyme 15-lipoxygenase-1 (15-LOX-1), critical in arachidonic acid metabolism, is implicated in various diseases, yet its specific role and precise mechanisms in PE remain largely unknown. In this study, we found that 15-LOX-1 and its main metabolite, 15-HETE, were significantly increased in both the placenta and serum of PE patients. This increase was accompanied by elevated levels of endothelial injury markers, including intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1). A positive correlation between 15-LOX-1 and those markers in the placenta. In Alox15-/- mice, Alox15 deficiency reduced endothelial cell injury in PE-like mice induced by L-NAME. In vitro studies showed that hypoxia-induced upregulation of 15-LOX-1 reduced the cell viability, migration, and angiogenesis of human umbilical vein endothelial cells (HUVECs), while increasing apoptosis and inflammatory cell adhesion. Mechanistically, the p38 MAPK pathway was identified as a downstream target of 15-LOX-1. Knocking down 15-LOX-1 or inhibiting p38 MAPK activation improved endothelial cell injury in hypoxia-treated HUVECs. Furthermore, downregulation of miR-26a-2-3p was found to correlate negatively and colocalize with 15-LOX-1 upregulation in the placenta of PE patients. Luciferase reporter assays further confirmed that miR-26a-2-3p directly bind to the 3'UTR of 15-LOX-1, targeting its expression. Moreover, miR-26a-2-3p agomir ameliorated the PE-like phenotype in mice through the 15-LOX-1/p38 MAPK axis, improving endothelial dysfunction. Therefore, our study provides novel insights into the pathogenesis of PE and highlight modulating the miR-26a-2-3p/15-LOX-1/p38 MAPK axis as a potential therapeutic target for PE.

Noncaloric monosaccharides induce excessive sprouting angiogenesis in zebrafish via foxo1a-marcksl1a signal.

Artificially sweetened beverages containing noncaloric monosaccharides were suggested as healthier alternatives to sugar-sweetened beverages. Nevertheless, the potential detrimental effects of these noncaloric monosaccharides on blood vessel function remain inadequately understood. We have established a zebrafish model that exhibits significant excessive angiogenesis induced by high glucose, resembling the hyperangiogenic characteristics observed in proliferative diabetic retinopathy (PDR). Utilizing this model, we observed that glucose and noncaloric monosaccharides could induce excessive formation of blood vessels, especially intersegmental vessels (ISVs). The excessively branched vessels were observed to be formed by ectopic activation of quiescent endothelial cells (ECs) into tip cells. Single-cell transcriptomic sequencing analysis of the ECs in the embryos exposed to high glucose revealed an augmented ratio of capillary ECs, proliferating ECs, and a series of upregulated proangiogenic genes. Further analysis and experiments validated that reduced foxo1a mediated the excessive angiogenesis induced by monosaccharides via upregulating the expression of marcksl1a. This study has provided new evidence showing the negative effects of noncaloric monosaccharides on the vascular system and the underlying mechanisms.

Consuming too much sugar can damage blood vessels and contribute to diseases like diabetes and heart disease. Artificial sweeteners have been suggested as a healthier alternative, and are now included in many products like sodas and baked goods. However, some studies have suggested that people who consume large amounts of artificial sweeteners also have an increased risk of cardiovascular disease. Others suggest individuals may also experience spikes in blood sugar levels similar to those observed in people with diabetes. Yet few studies have examined how artificial sweeteners affect the network of vessels that transport blood and other substances around the body. To investigate this question, Wang, Zhao, Xu, et al. studied zebrafish embryos which had been exposed to sugar and a type of artificial sweetener known as non-caloric monosaccharides. Various imaging tools revealed that high levels of sugar caused the embryos to produce more new blood vessels via a process called angiogenesis. This excessive growth of blood vessels has previously been linked to diabetic complications, including cardiovascular disease. Wang, Zhao, Xu, et al. found that zebrafish embryos exposed to several different non-caloric monosaccharides developed similar blood vessel problems. All the sweeteners tested caused immature cells lining the blood vessels to develop into active tip cells that promote angiogenesis. This led to more new blood vessels forming that branch off already existing veins and arteries. These findings suggest that artificial sweeteners may cause the same kind of damage to blood vessels as sugar. This may explain why people who consume a lot of artificial sweeteners are at risk of developing heart disease and high blood sugar levels. Future studies could help scientists learn more about how genetics or other factors affect the health impact of sugars and artificial sweeteners. This may lead to a greater understanding of the long-term health effects of artificially sweetened foods.

The role of oligodendrocyte progenitor cells in the spatiotemporal vascularization of the human and mouse neocortex.

Brain vasculature formation begins with vessel invasion from the perineural vascular plexus, which expands through vessel sprouting and growth. Recent studies have indicated the existence of oligodendrocyte-vascular crosstalk during development. However, the relationship between oligodendrocyte progenitor cells (OPCs) and the ordered spatiotemporal vascularization of the neocortex has not been elucidated. Our findings suggest that OPCs play a complex role in the vessel density of the embryonic and postnatal neocortex. Analyses of normal human and mouse embryonic cerebral cortex show that vascularization and OPC distribution are tightly controlled in a spatially and temporally restricted manner, exhibiting a positive correlation. Loss of OPCs at both embryonic and postnatal stages led to a reduction in vascular density, suggesting that OPC populations play a role in vascular density. Nonetheless, dynamic observation on cultured brain slices and staining of tissue sections indicate that OPC migration is unassociated with the proximity to blood vessels, primarily occurring along radial glial cell processes. Additionally, in vitro experiments demonstrate that OPC secretions promote vascular endothelial cell (VEC) growth. Together, these observations suggest that vessel density is influenced by OPC secretions.

Identifying specific functional roles for senescence across cell types.

Cellular senescence plays critical roles in aging, regeneration, and disease; yet, the ability to discern its contributions across various cell types to these biological processes remains limited. In this study, we generated an in vivo genetic toolbox consisting of three p16Ink4a-related intersectional genetic systems, enabling pulse-chase tracing (Sn-pTracer), Cre-based tracing and ablation (Sn-cTracer), and gene manipulation combined with tracing (Sn-gTracer) of defined p16Ink4a+ cell types. Using liver injury and repair as an example, we found that macrophages and endothelial cells (ECs) represent distinct senescent cell populations with different fates and functions during liver fibrosis and repair. Notably, clearance of p16Ink4a+ macrophages significantly mitigates hepatocellular damage, whereas eliminating p16Ink4a+ ECs aggravates liver injury. Additionally, targeted reprogramming of p16Ink4a+ ECs through Kdr overexpression markedly reduces liver fibrosis. This study illuminates the functional diversity of p16Ink4a+ cells and offers insights for developing cell-type-specific senolytic therapies in the future.

Glutamine synthetase accelerates re-endothelialization of vascular grafts by mitigating endothelial cell dysfunction in a rat model.

Endothelial cell (EC) dysfunction within the aorta has long been recognized as a prominent contributor to the progression of atherosclerosis and the subsequent failure of vascular graft transplantation. However, the direct relationship between EC dysfunction and vascular remodeling remains to be investigated. In this study, we sought to address this knowledge gap by employing a strategy involving the release of glutamine synthetase (GS), which effectively activated endothelial metabolism and mitigates EC dysfunction. To achieve this, we developed GS-loaded small-diameter vascular grafts (GSVG) through the electrospinning technique, utilizing dual-component solutions consisting of photo-crosslinkable hyaluronic acid and polycaprolactone. Through an in vitro model of oxidized low-density lipoprotein-induced injury in human umbilical vein endothelial cells (HUVECs), we provided compelling evidence that the GSVG promoted the restoration of motility, angiogenic sprouting, and proliferation in dysfunctional HUVECs by enhancing cellular metabolism. Furthermore, the sequencing results indicated that these effects were mediated by miR-122-5p-related signaling pathways. Remarkably, the GSVG also exhibited regulatory capabilities in shifting vascular smooth muscle cells towards a contractile phenotype, mitigating inflammatory responses and thereby preventing vascular calcification. Finally, our data demonstrated that GS incorporation significantly enhanced re-endothelialization of vascular grafts in a ferric chloride-injured rat model. Collectively, our results offer insights into the promotion of re-endothelialization in vascular grafts by restoring dysfunctional ECs through the augmentation of cellular metabolism.

Dexrazoxane prevents vascular toxicity in doxorubicin-treated mice.

BACKGROUND: Doxorubicin (DOX) is used for breast cancer and lymphoma, but can cause cardiotoxicity, arterial stiffness, and endothelial dysfunction. We recently reported SERPINA3N as biomarker of cardiovascular toxicity in patients and mice. Dexrazoxane (DEXRA) is an FDA-approved drug that prevents DOX-induced cardiac toxicity in high-risk patients. However, the effect of DEXRA on vascular dysfunction during DOX treatment has not been documented. Therefore, here we investigated whether DEXRA protects against DOX-induced arterial stiffness, endothelial dysfunction, and SERPINA3N upregulation in tissue and plasma from mice. METHODS: Male C57BL6/J mice were treated with DOX (4 mg/kg), DEXRA (40 mg/kg), a combination (DEXRA + DOX), or VEHICLE (0.9% NaCl) weekly i.p. for 6 weeks (n = 8 per group). Cardiovascular function was measured in vivo by ultrasound imaging at baseline, weeks 2 and 6. Vascular reactivity was analyzed ex vivo in the thoracic aorta at week 6 and molecular analysis was performed. RESULTS: DEXRA prevented left ventricular ejection fraction decline by DOX (DEXRA + DOX: 62 ± 2% vs DOX: 51 ± 2%). Moreover, DEXRA prevented the increase in pulse wave velocity by DOX (DEXRA + DOX: 2.1 ± 0.2 m/s vs DOX: 4.5 ± 0.3 m/s) and preserved endothelium-dependent relaxation (DEXRA + DOX: 82 ± 3% vs DOX: 62 ± 3%). In contrast to DOX-treated mice, SERPINA3N did not increase in the DEXRA + DOX group. CONCLUSION: Our results not only confirm the cardioprotective effects of DEXRA against DOX-induced cardiotoxicity but also add preservation of vascular endothelial cell function as an important mechanism. Moreover, the study demonstrates the potential of SERPINA3N as a biomarker for monitoring cardiovascular complications of DOX in high-risk patients.

Loss of Nr4a1 ameliorates endothelial cell injury and vascular leakage in lung transplantation from circulatory-death donor.

BACKGROUND: Ischemia-reperfusion injury (IRI) stands as a major trigger for primary graft dysfunction (PGD) in lung transplantation (LTx). Especially in LTx from donation after cardiac death (DCD), effective control of IRI following warm ischemia (WIRI) is crucial to prevent PGD. This study aimed to identify the key factors affecting WIRI in LTx from DCD. METHODS: Previously reported RNA-sequencing dataset of lung WIRI was reanalyzed to identify nuclear receptor subfamily 4 group A member 1 (NR4A1) as the immediate early gene for WIRI. Dynamics of NR4A1 expression were verified using a mouse hilar clamp model. To investigate the role of NR4A1 in WIRI, a mouse model of LTx from DCD was established using Nr4a1 knockout (Nr4a1-/-) mice. RESULTS: NR4A1 was located around vascular cells, and its protein levels in the lungs increased rapidly and transiently during WIRI. LTｘ from Nr4a1-/- donors significantly improved pulmonary graft function compared to wild-type donors (P < 0.001). Histological analysis showed decreased microvascular endothelial cell death (P = 0.007), neutrophil infiltration (P < 0.001), and albumin leakage (P < 0.001). Evans blue permeability assay demonstrated maintained pulmonary microvascular barrier integrity in grafts from Nr4a1-/- donors, correlating with diminished pulmonary edema (P < 0.001). However, NR4A1 did not significantly affect the inflammatory response during WIRI, and IRI was not suppressed when a wild-type donor lung was transplanted into the Nr4a1-/- recipient. CONCLUSIONS: Donor NR4A1 plays a specialized role in the positive regulation of endothelial cell injury and microvascular hyperpermeability. These findings demonstrate the potential of targeting NR4A1 interventions to alleviate PGD and improve outcomes in LTx from DCD.

Transmission electron microscopy of transbronchial lung cryobiopsy samples in a cohort of fibrotic interstitial lung disease patients - feasibility and implications of endothelial alterations.

We evaluated the utility of transmission electron microscopy (TEM) in transbronchial lung cryobiopsy (TBLC) samples from 16 consecutive patients undergoing routine evaluation of fibrotic interstitial lung disease (ILD). Next to routine pathology examination, 1 to 2 TBLC samples were prepared for TEM analysis and evaluated using a Zeiss LEO EM 910. Subpleural cryobiopsies and unfrozen excision biopsies from fresh lobectomy tissue of non-ILD lung cancer patients served as controls. TEM provided high-quality images with only minor cryoartifacts as compared to controls. Furthermore, in several ILD patients we found marked microvascular endothelial abnormalities like luminal pseudopodia-like protrusions and inner surface defects. These were extensively present in four (25%), moderately present in seven (43.8%), and largely absent in five (31.3%) patients. A higher degree of TEM endothelial abnormalities was associated with younger age, non-specific interstitial pneumonia pattern, higher broncho-alveolar lavage lymphocyte count, positive autoantibodies, and lower spirometry, diffusion capacity and oxygenation biomarkers. We conclude that TEM evaluation of TBLC samples from ILD patients is feasible, while the observed microvascular alterations warrant further evaluation.

Endocan, a novel glycoprotein with multiple biological activities, may play important roles in neurological diseases.

Endothelial cell specific-1 (ESM-1), also known as endocan, is a soluble dermatan sulfate proteoglycan that is mainly secreted by endothelial cells. Endocan is associated with tumorigenesis and cancer progression and is also related to cardiovascular disorders, autoimmune diseases, and sepsis. The phenylalanine-rich region and linear polysaccharide of endocan are necessary for the protein to exert its biological functions. Elevated plasma endocan levels reflect endothelial activation and dysfunction. In addition, endocan participates in complex inflammatory responses and proliferative processes. Here, we reviewed current research on endocan, elaborated the protein's structure and biological functions, and speculated on its possible clinical value in nervous system diseases. We conclude that endocan may be a glycoprotein that plays an important role in neurological disorders.

Development of pial collaterals by extension of pre-existing artery tips.

Pial collaterals provide protection from ischemic damage and improve the prognosis of stroke patients. The origin or precise sequence of events underlying pial collateral development is unclear and has prevented clinicians from adapting new vascularization and regeneration therapies. We use genetic lineage tracing and intravital imaging of mouse brains at cellular resolution to show that during embryogenesis, pial collateral arteries develop from extension and anastomoses of pre-existing artery tips in a VegfR2-dependent manner. This process of artery tip extension occurs on pre-determined microvascular tracks. Our data demonstrate that an arterial receptor, Cxcr4, earlier shown to drive artery cell migration and coronary collateral development, is dispensable for the formation and maintenance of pial collateral arteries. Our study shows that collateral arteries of the brain are built by a mechanism distinct from that of the heart.

A Promising Therapeutic Strategy of Combining Acoustically Stimulated Nanobubbles and Existing Cancer Treatments.

In recent years, ultrasound-stimulated microbubbles (USMBs) have gained great attention because of their wide theranostic applications. However, due to their micro-size, reaching the targeted site remains a challenge. At present, ultrasound-stimulated nanobubbles (USNBs) have attracted particular interest, and their small size allows them to extravasate easily in the blood vessels penetrating deeper into the tumor vasculature. Incorporating USNBs with existing cancer therapies such as chemotherapy, immunotherapy, and/or radiation therapy in several preclinical models has been demonstrated to have a profound effect on solid tumors. In this review, we provide an understanding of the composition and formation of nanobubbles (NBs), followed by the recent progress of the therapeutic combinatory effect of USNBs and other cancer therapies in cancer treatment.

Association of Endothelial Cell Activation with Acute Kidney Injury during Coronary Angiography and the Influence of Recombinant Human C1 Inhibitor-A Secondary Analysis of a Randomized, Placebo-Controlled, Double-Blind Trial.

BACKGROUND: Acute kidney injury (AKI) as a result of iodinated contrast media (CM) has been linked to CM-induced renal ischemia and toxic effects on endothelial cells (EC). The recombinant human C1 inhibitor (rhC1INH) has been shown to influence EC activation. METHODS: Secondary analysis of 74/77 (96%) participants of a double-blind, randomized, and placebo-controlled study that assessed the effect of rhC1INH on AKI. E-selectin, intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule (VCAM-1), and CC-chemokin-ligand-5 (CCL5) were determined in frozen blood samples over 48 h and analyzed according to the treatment group and renal outcomes. RESULTS: The mean age was 76.7 years, and 37 patients each received rhC1INH and placebo, respectively. In the entire study population, minor differences in median EC activation markers/CCL5 concentrations during the first 48 h compared to baseline were observed (e.g., E-selectin 27.5 ng/mL at baseline vs. 29.7 ng/mL on day 1, CCL5: 17.7 ng/mL at baseline vs. 32.2 ng/mL on day 2). Absolute changes in ICAM-1/E-selectin concentrations correlated with a higher peak change in urinary NGAL concentrations. However, AKI was not associated with significant changes in EC markers/CCL5. Last, no significant differences in serum concentrations of EC activation markers/CCL5 were evident between the placebo and the rhC1INH group. CONCLUSIONS: CM administration during coronary angiography only mildly activated ECs within the first 48 h, which does not explain subsequent AKI. The administration of rhC1INH was not associated with a reduction of EC activation or CCL5.

Investigation of Type A Aortic Dissection Using Computational Modelling.

Aortic dissection is a catastrophic failure of the endothelial wall that could lead to malperfusion or rupture. Computational modelling tools may help detect arterial damage. Technological advancements have led to more sophisticated forms of modelling being made available to low-grade computers. These devices can create 3D models with clinical data, where the clinical blood pressure waveforms' model can be used to form boundary conditions for assessing hemodynamic parameters, modelling blood flow propagation along the aorta to predict the development of cardiovascular disease. This study presents patient-specific data for a rare case of severe Type A aortic dissection. CT scan images were taken nine months apart, consisting of the artery both before and after dissection. The results for the pre-dissection CT showed that the pressure waveform at the ascending aorta was higher, and the systolic pressure was lagging at the descending aorta. For the post-dissection analysis, we observed the same outcome; however, the amplitude for the waveform (systolic pressure) at the ascending aorta increased in the false lumen by 25% compared to the true lumen by 3%. Also, the waveform peak (systolic) was leading by 0.01 s. The hemodynamic parameter of wall shear stress (WSS) predicted the aneurysm's existence at the ascending aorta, as well as potential aortic dissection. The high WSS contours were located at the tear location at the peak blood flow of 0.14 s, which shows the potential of this tool for earlier diagnosis of aortic dissection.

Pan-cancer integrative analyses dissect the remodeling of endothelial cells in human cancers.

Therapeutics targeting tumor endothelial cells (TECs) have been explored for decades, with only suboptimal efficacy achieved, partly due to an insufficient understanding of the TEC heterogeneity across cancer patients. We integrated single-cell RNA-seq data of 575 cancer patients from 19 solid tumor types, comprehensively charting the TEC phenotypic diversities. Our analyses uncovered underappreciated compositional and functional heterogeneity in TECs from a pan-cancer perspective. Two subsets, CXCR4 + tip cells and SELE + veins, represented the prominent angiogenic and proinflammatory phenotypes of TECs, respectively. They exhibited distinct spatial organization patterns, and compared to adjacent non-tumor tissues, tumor tissue showed an increased prevalence of CXCR4 + tip cells, yet with SELE + veins depleted. Such functional and spatial characteristics underlie their differential associations with the response of anti-angiogenic therapies and immunotherapies. Our integrative resources and findings open new avenues to understand and clinically intervene in the tumor vasculature.

Impaired microvascular function in patients with sickle cell anemia and leg ulcers improved with healing.

Leg Ulcer (LU) pathophysiology is still not well understood in sickle cell anaemia (SCA). We hypothesised that SCA patients with LU would be characterised by lower microvascular reactivity. The aim of the present study was to compare the microcirculatory function (transcutaneous oxygen pressure (TcPO2) on the foot and laser Doppler flowmetry on the arm) and several blood biological parameters between nine SCA patients with active LU (LU+) and 56 SCA patients with no positive history of LU (LU-). We also tested the effects of plasma from LU+ and LU- patients on endothelial cell activation. We observed a reduction of the TcPO2 in LU+ compared to LU- patients. In addition, LU+ patients exhibited lower cutaneous microvascular vasodilatory capacity in response to acetylcholine, current and local heating compared to LU- patients. Inflammation and endothelial cell activation in response to plasma did not differ between the two groups. Among the nine patients from the LU+ group, eight were followed and six achieved healing in 4.4 ± 2.5 months. Among thus achieving healing, microvascular vasodilatory capacity in response to acetylcholine, current and local heating and TcPO2 improved after healing. In conclusion, microcirculatory function is impaired in patients with LU, and improves with healing.

Ulinastatin attenuated cardiac ischaemia/reperfusion injury by suppressing activation of the tissue kallikrein-kinin system.

BACKGROUND AND PURPOSE: Ulinastatin has beneficial effects in patients undergoing coronary artery bypass grafting (CABG) surgery due to its anti-inflammatory properties, but the underlying mechanism remains unclear. EXPERIMENTAL APPROACH: We used samples from patients undergoing CABG, a model of cardiac ischaemia-reperfusion injury (IRI) in mice and murine cardiac endothelial cell cultures to investigate links between ulinastatin, the kallikrein-kinin system (KKS), endothelial dysfunction and cardiac inflammation in the response to ischaemia/reperfusion injury (IRI). These links were assessed using clinical investigations, in vitro and in vivo experiments and RNA sequencing analysis. KEY RESULTS: Ulinastatin inhibited the activity of tissue kallikrein, a key enzyme of the KKS, at 24 h after CABG surgery, which was verified in our murine cardiac ischaemia-reperfusion model. Under normal conditions, ulinastatin only inhibited kallikrein activity but did not affect bradykinin (B1/B2) receptors. Ulinastatin protected against IRI, in vivo and in vitro, by suppressing activation of the kallikrein-kinin system and down-regulating B1/B2 receptor-related signalling pathways including ERK/ iNOS, which resulted in enhanced endothelial barrier function, mitigation of inflammation and oedema, decreased infarct size, improved cardiac function and decreased mortality. Inhibition of kallikrein and knockdown of B1, but not B2 receptors prevented ERK translocation into the nucleus, reducing reperfusion-induced injury in murine cardiac endothelial cells. CONCLUSIONS AND IMPLICATIONS: Treatment with ulinastatin exerts a protective influence on cardiac reperfusion by suppressing activation of the kallikrein-kinin system. Our findings highlight the potential of targeting kallikrein /bradykinin receptors to alleviate endothelial dysfunction, thus improving cardiac IRI.