Vascular Permeability Research Articles

Immunogenic effects of enamel matrix derivative on human alveolar ridge mucosa-derived vascular endothelial cells under lipopolysaccharide stimulation.

Early peri-implant disease detection remains difficult. Enamel matrix derivative (EMD), which is used for periodontal tissue regeneration, promotes leukocyte chemotactic factor and adhesion molecule expression in vascular endothelial cells. We hypothesized that stimulating vascular endothelial cells with EMD would induce an inflammatory response in the peri-implant mucosa, enabling early peri-implant infection detection. To verify this hypothesis, we assessed the intercellular adhesion between human alveolar ridge mucosa-derived vascular endothelial cells (ARMEC) stimulated with lipopolysaccharide (LPS) and EMD and human periodontal ligament-derived vascular endothelial cells (PDLEC). Leukocyte chemotactic factors and cell adhesion molecules were investigated and we established an experimental model of peri-implant disease by stimulating ARMEC (representing the peri-implant mucosa) with Porphyromonas gingivalis-derived LPS. ARMEC and PDLEC were obtained from patients (n = 6) who visited the Nippon Dental University Niigata Hospital. The cells were divided into four subcategories, each cultured with: LPS (1µg/mL), EMD (100µg/mL), LPS + EMD, and pure medium. Cell viability, leukocyte chemotactic factor (interleukin-8: IL-8), adhesion molecules (intercellular adhesion molecule-1: ICAM-1), tight junction protein gene expression (zonula occludens-1: ZO-1 and Occludin), and transendothelial electrical resistance (TEER) was then determined. LPS reduced ARMEC viability, whereas simultaneous stimulation with EMD improved it. LPS and EMD stimulation enhanced IL-8 and ICAM-1 gene expression, suppressed TEER, and decreased ZO-1 and Occludin expression levels compared to that with stimulation with LPS alone. EMD stimulates leukocyte migration, increase vascular permeability, and trigger an immune response in the peri-implant mucosa, thus facilitating the early detection and treatment of peri-implant disease.

Capillary rise in partially saturated rigid porous media

We explore predictions of two models of one-dimensional capillary rise in rigid and partially saturated porous media. One is an existing one from the literature and the second is a free-boundary model based on Richards’ equation with two moving boundaries of the evolving partially saturated region. Both models involve the specification of saturation-dependent functions for local capillary pressure and permeability and connect to classical models for saturated porous media. Existing capillary-rise experiments show two notable regimes: (i) an early-time regime typically well-described by classical capillary-rise theory in a fully saturated porous media, and (ii) a long-time regime that has anomalous dynamics in which the capillary-rise height may scale with a non-classical power law in time or have more complicated dynamics. We demonstrate that the predictions of both models compare well with experimental capillary-rise data over early- and long-time regimes gathered from three independent studies in the literature. The model predictions also shed light on recent scaling laws that relate the capillary pressure and permeability of the partially saturated media to the capillary-rise height. We use these models to probe computationally observed permeability relationships to capillary-rise height. We demonstrate that a recently proposed permeability scaling for the anomalous capillary-rise regime is indeed realized and is particularly apparent in the lower portion of the partially saturated media. For our free-boundary model we also compute capillary pressure measures and show that these reveal the linear relation between the capillary pressure and capillary-rise height expected for a capillarity–gravity balance in the upper portion of the partially saturated porous media.

Clinical features and potential markers of disease in idiopathic non-histaminergic angioedema, a real-life study.

Idiopathic non-histaminergic acquired angioedema (InH-AAE) is a rare disease, with unknown etiology and pathogenesis, characterized by recurrent clinical manifestations and resistance to antihistamines and corticosteroids. We aim to evaluate clinical features and potential markers of disease in an Italian cohort of patients with InH-AAE. We enrolled 26 patients diagnosed with InH-AAE. Information about clinical features, treatments, routine laboratory investigations, immunological and genetic tests were collected. We assessed plasma levels of complement components, angiogenic and lymphangiogenic mediators, proinflammatory cytokines and chemokines, and activity of phospholipases A2. Finally, patients underwent nailfold videocapillaroscopy (NVC); both quantitative and qualitative capillaroscopic parameters were analyzed. Plasma levels of VEGFs were similar in healthy controls and in InH-AAE patients. ANGPT1 was decreased in InH-AAE patients compared to controls while ANGPT2 was similar to controls. Interestingly, the ANGPT2/ANGPT1 ratio (an index of vascular permeability) was increased in InH-AAE patients compared to controls. sPLA2 activity, elevated in patients with C1-INH-HAE, showed differences also when measured in InH-AAE patients. TNF-α concentration was higher in InH-AAE patients than in healthy controls, conversely, the levels of CXCL8, and IL-6 were similar in both groups. At the NVC, the capillary loops mainly appeared short and tortuous in InH-AAE patients. InH-AAE represents a diagnostic challenge.Due to the potential life-threatening character of this condition, a prompt identification of the potentially bradykinin-mediated forms is crucial. A better comprehension of the mechanism involved in InH-AAE would also lead to the development of new therapeutic approaches to improve life quality of patients affected by this disabling disease.

Cardio- and Vasoprotective Effects of Quinacrine in an In Vivo Rat Model of Myocardial Ischemia/Reperfusion Injury.

This study aimed to investigate the cardioprotective effect of quinacrine in an in vivo model of myocardial ischemia/reperfusion injury. A 30-min regional myocardial ischemia followed by a 2-h reperfusion was modeled in anesthetized Wistar rats. Starting at the last minute of ischemia and during the first 9 min of reperfusion the rats in the control (n=8) and experimental (n=9) groups were injected with 0.9% NaCl and quinacrine solution (5 mg/kg), respectively. The area at risk and infarct size were evaluated by "double staining" with Evans blue and triphenyltetrazolium chloride. To assess vascular permeability in the area at risk zone, indocyanine green (ICG) and thioflavin S (ThS) were injected intravenously at the 90th and 120th minutes of reperfusion, respectively, to assess the no-reflow zone. The images of ICG and ThS fluorescence in transverse sections of rat hearts were obtained using a FLUM multispectral fluorescence organoscope. HR tended to decrease by 13% after intravenous administration of quinacrine and then recovered within 50 min. Quinacrine reduced the size of the necrotic zone (p=0.01), vascular permeability in the necrosis region, and the no-reflow area (p=0.027); at the same time, the area at risk did not significantly differ between the groups. Intravenous administration of quinacrine at the beginning of reperfusion of the rat myocardium reduces no-reflow phenomenon and infarct size.

Analgesic and anti-inflammatory activity of Cotinus coggygria Scop. extracts in vivo

Objective: To assess the analgesic and anti-inflammatory effects of standardized extract of Cotinus coggygria (C. coggygria) in different animal models. Methods: C. coggygria extracts (25, 50, and 100 mg/kg) were administered to rats and mice (n=6) during hot plate, tail-flick, acetic acid-induced writhing, and formalin tests to determine its analgesic efficacy. The anti-inflammatory activity of C. coggygria extracts was evaluated by histamine and carrageenan-induced paw edema, cotton pellet-induced granuloma, and acetic acid-induced peritoneal capillary dye leakage tests. Results: C. coggygria extracts (50 and 100 mg/kg) significantly alleviated thermal and chemical-induced pain in rodents (P<0.05). It also demonstrated notable anti-inflammatory properties by mitigating histamine and carrageenan-induced paw edema, granuloma deposits, and vascular permeability (P<0.05). Moreover, C. coggygria extracts remarkably reduced TNF-α, IL-1β, IL-6, COX-2, and oxidative stress in rat paws (P<0.05). Carrageenan-induced histological aberrations in hind paw tissues were effectively (P<0.05) mitigated by treatment with C. coggygria extracts. Conclusions: C. coggygria Scop. extracts show analgesic and anti-inflammatory effects via inhibition of COX-2 and inflammatory and oxidative mediators.

Decorrelation Time Mapping as an Analysis Tool for Nanobubble-Based Contrast Enhanced Ultrasound Imaging.

Nanobubbles (NBs; ~100-500 nm diameter) are preclinical ultrasound (US) contrast agents that expand applications of contrast enhanced US (CEUS). Due to their sub-micron size, high particle density, and deformable shell, NBs in pathological states of heightened vascular permeability (e.g. in tumors) extravasate, enabling applications not possible with microbubbles (~1000-10,000 nm diameter). A method that can separate intravascular versus extravascular NB signal is needed as an imaging biomarker for improved tumor detection. We present a demonstration of decorrelation time (DT) mapping for enhanced tumor NB-CEUS imaging. In vitro models validated the sensitivity of DT to agent motion. Prostate cancer mouse models validated in vivo imaging potential and sensitivity to cancerous tissue. Our findings show that DT is inversely related to NB motion, offering enhanced detail of NB dynamics in tumors, and highlighting the heterogeneity of the tumor environment. Average DT was high in tumor regions (~9 s) compared to surrounding normal tissue (~1 s) with higher sensitivity to tumor tissue compared to other mapping techniques. Molecular NB targeting to tumors further extended DT (11 s) over non-targeted NBs (6 s), demonstrating sensitivity to NB adherence. From DT mapping of in vivo NB dynamics we demonstrate the heterogeneity of tumor tissue while quantifying extravascular NB kinetics and delineating intra-tumoral vasculature. This new NB-CEUS-based biomarker can be powerful in molecular US imaging, with improved sensitivity and specificity to diseased tissue and potential for use as an estimator of vascular permeability and the enhanced permeability and retention (EPR) effect in tumors.

Protective effect and mechanism of resveratrol on vascular endothelial cells

Resveratrol is a polyphenolic plant extract with many biological activities such as anti-inflammation and anti-oxidative stress. Vascular endothelial cell (VEC) is the main sites for maintaining normal vascular permeability and participating in vasomotor regulation and substance exchange. VEC injury plays a key role in various diseases or pathological processes such as cardiovascular disease, chronic inflammation and sepsis. Studies have shown that resveratrol protects VEC and reduces endothelial damage by regulating nitric oxide (NO) and its related enzymes, reducing oxidative stress and inhibiting apoptosis, thereby exerting beneficial effects.

The current pathogenicity and potential risk evaluation of Crimean-Congo hemorrhagic fever virus to cause mysterious "Disease X"-An updated literature review.

Crimean-Congo hemorrhagic fever (CCHF) is a severe and potentially lethal illness. Tick bites of the Hyalomma genus are the primary source of transmission of CCHF to humans. The virus responsible for CCHF is the CCHF virus (CCHFV). It is a single-stranded negative sensed RNA virus. The virus belongs to the Orthonairoviridae genus within the Nairoviridae family. It occurs in an extensive geographical area spanning the Middle East, western China, southern Asia, southeastern Europe, and much of Africa. The current study aimed to evaluate the pathogenicity and potential risk of CCHFV to cause a public health emergency of international concern. We searched updated relevant information from PubMed, Google Scholar, and Scopus databases using Crimean-Congo hemorrhagic fever, tick-borne virus, and Nairovirus as keywords. The case fatality rate (CFR) varies by region. It can be more than 30% in some cases. Three segments in the genome of CCHFV (L, M, and S) are different in size and function. It is unknown whether the pathogenicity of CCHFV varied based on the genomic diversity. CCHFV can be transmitted through tick bites, handling of infected ticks, contact with infected humans, contaminated body fluids, and so on. A wide range of severity is associated with CCHF, ranging from a moderate fever with no apparent cause to increased vascular permeability, failure of several organs, bleeding, and shock. Hospitals with high-level isolation units should be the first choice for treating CCHF patients. Individual safety equipment is crucial in healthcare to prevent the spread of the virus. In the farm environment, using integrated pest management techniques, minimizing activity in tick-infested regions, and dressing appropriately in long sleeves and pants will help to reduce the risk of CCHFV infection via tick bites. There are no approved vaccinations or therapeutics for CCHF except supportive therapeutic approaches. Therefore, scientists recommend early ribavirin therapy for cases of high-risk exposures.

GMPR2-MDA5 interaction bridged the cell junction and anti-GCRV immune

As a consequence of increased vascular endothelial permeability and vascular injury caused by GCRV (grass carp reovirus) infection, grass carp (Ctenopharyngodon idellus) could suffer from hemorrhagic disease and even death. MDA5 is a key RNA sensor that stimulates type I interferon as well as regulates vascular permeability. The guano monophosphate ductase 2 (GMPR2) plays a key role in regulating the permeability of vascular endothelial cells. This study examined the interaction between grass carp MDA5 and GMPR2 and their antiviral effects. GMPR2 interacted directly with MDA5 and promoted its protein level, whilst MDA5 conversely inhibited the GMPR2 protein expression. The expression of GCRV VP7 protein was inhibited by the increased levels of MDA5 and GMPR2. In addition, the cell junction molecule Claudin7b which is closely related to the change in vascular permeability, was inhibited by both MDA5 and GMPR2. Finally, in GMPR2 knockout zebrafish, the mRNA level of MDA5 was significantly down-regulated, which validated the positive functional relationship of GMPR2 on MDA5. Consistent changes of the Claudin 7b and VP7 protein levels were observed in the GMPR2 and MDA5 overexpression groups. In summary, MDA5-GMPR2 interaction affecting GCRV replication might through cell junction molecule Claudin7b. The results from this study provided systematic support for revealing the genetic basis of cell permeability change as well as the hemorrhagic diseases in grass carp.

Cystoid Macular Edema (CME)

Cystoid Macular Edema (CME) is one of the most common causes of vision loss in postoperative cataract patients. CME occurs due to fluid accumulation in the subretinal space due to increased permeability of perifoveal capillaries and intra-ocular vascular instability which is a consequence of disruption or damage to the blood barrier layer of the retina. This condition occurs in 20% after cataract surgery, 1% of whom have clinical symptoms in the form of a significant decrease in vision. Provision of medicamentose therapy after surgery can optimize sharp vision and treat CME. The patient who entered from the poly RSUDZA was an 82-year-old man with complaints of blurred left eye and winding vision since the patient sneezed 1 week after cataract surgery. Patients are given artificial tears eye drops and topical NSAIDs as well as education for drug adherence. The response to therapy is quite good where there is improvement in vision and on OCT examination there is a reduction in macular thickness.

Tumour-derived Extracellular Vesicle and Particle Reprogramming of Interstitial Macrophages in the Lung Pre-Metastatic Niche Enhances Vascular Permeability and Metastatic Potential.

Extracellular vesicles and particles (EVPs) are pivotal mediators of pre-metastatic niche formation and cancer progression, including induction of vascular permeability, which facilitates tumor cell extravasation and metastasis. However, the mechanisms through which EVPs exert this effect remain poorly understood. Here, we elucidate a novel mechanism by which tumor EVPs enhance endothelial cell permeability, tumor extravasation, and lung metastasis to different degrees, depending on tumor type. Strikingly, vascular leakiness is observed within 48h following tumor implantation and as early as one hour following intravenous injection of tumour-derived EVPs in naïve mice. Surprisingly, rather than acting directly on endothelial cells, EVPs first activate interstitial macrophages (IMs) leading to activation of JAK/STAT signaling and IL-6 secretion in IMs which subsequently promote endothelial permeability. Depletion of IMs significantly reduces tumour-derived EVP-dependent vascular leakiness and metastatic potential. Tumour EVPs that strongly induce vascular leakiness express high levels of ITGα5, and ITGα5 ablation impairs IM activation, cytokine secretion, and subsequently vascular permeability and metastasis. Importantly, IL-6 expression is elevated in IMs from non-involved tumor-adjacent lung tissue compared to distal lung tissue in lung cancer patients, highlight the clinical relevance of our discovery. Our findings identify a key role for IM activation as an initiating step in tumor type-specific EVP-driven vascular permeability and metastasis, offering promising targets for therapeutic intervention.

FABP4 as potential indicator for GDM-induced fetal endothelial dysfunction

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): DFG project no. 288034826—International Research Training Group (IRTG) 2251 Background Gestational diabetes mellitus (GDM) is linked to an elevated risk of developing cardiovascular diseases (CVD) both for the mother and the baby in later life. Previous studies have identified fatty acid-binding protein 4 (FABP4) as a prime candidate involved in the pathophysiology of GDM. FABP4 is known to promote an inflammatory response and vascular permeability, induce oxidative stress in endothelial cells (ECs), and impair the nitric oxide signaling pathway, thereby promoting endothelial dysfunction. Indeed, women with GDM exhibit elevated blood levels of FABP4, suggesting its potential as a biomarker for endothelial dysfunction and cardiovascular risk assessment in GDM. However, the role that FABP4 plays in the fetal endothelial function remains poorly understood. Purpose Thus, our aim is to understand the role of FABP4 in fetal endothelial dysfunction and its regulation to mitigate the impact of GDM on the vasculature. Methods Fetoplacental vessels and primary human umbilical vein endothelial cells (HUVECs) were isolated from placentas and umbilical cords obtained from both normoglycemic (NG) and GDM pregnancies. We also obtained the clinical data from the mothers and collected the cord blood. Total mRNA from HUVECs was used for bulk RNA sequencing to compare gene expression, while gene expression analysis in the vessels was conducted using RT-qPCR. Additionally, NG HUVECs were pooled and cultured under high laminar flow conditions (30 dyn/cm²) or subjected to various treatments, including insulin (5nM), glucose (25mM), simvastatin (10nm), or VEGF-A stimulation. Subsequent RT-qPCRs were performed to analyze the gene expression of several genes of interest. Results The bulk RNA sequencing data analysis revealed FABP4 as an overexpressed gene in GDM HUVECs compared to NG. Furthermore, the analysis of data through Gene Set Enrichment Analysis provided a list of different gene sets that are enriched in GDM samples. Among these gene sets are pathways or processes implicated in endothelial dysfunction, such as angiogenesis, PI3K/AKT/mTOR signaling, reactive oxygen species pathway, or inflammatory response. In vitro experiments provided evidence for an elevated FABP4 mRNA expression after VEGF treatment of HUVECs. Conversely, both simvastatin treatment and exposure to laminar flow reduced FABP4 mRNA expression and increased eNOS expression, suggesting a potential inhibitory effect of nitric oxide on FABP4. Conclusion We provided evidence that FABP4 could be involved in fetal GDM-induced endothelial dysfunction. Shear stress and statins might protect the endothelium against the negative impact of FABP4.

Ayurvedic herbal formulations Haridra Khanda and Manjisthadi Kwath (brihat) in the management of allergic rhinitis: A pharmacological study

This study aims to pharmacologically validate Haridra Khanda (HK) and Manjishthadi Kwatham (brihat) (MMK) in allergy management using invivo and invitro studies to rationalize the prescription of these two ayurvedic polyherbal drug formulations, which are currently used in Indian government hospitals. Experimental animals received HK and MMK orally from day 0 to day 14 and histamine (1 mg/kg b.w/i.v) and 1 % evans blue (EB) (0.1 mL) via tail vein on day 14. The compound 48/80 (intracutaneous) challenged mice model followed the same technique. The former mimicked acute anaphylaxis and the latter mast cell degranulation. For both models, EB dye leakage was quantified spectrophotometrically to determine vascular permeability. Plasma histamine was measured in Compound 48/80-induced animals using LC-ESI-MS/MS. The guineapig received HK and MMK p.o. and 0.6 % histamine sprayed in a histamine chamber to simulate allergic rhinitis. Blood eosinophil count and sneeze rate were measured in histamine-challenged guineapigs. Goat R.B.C. membrane stability assay (mammalian cell membrane toxicity) and intracellular histamine-induced cytosolic Ca2+ release assay in Chinese hamster ovary (CHO) cells were performed in vitro. For both histamine and Compound 48/80 challenged animals, HK (22.81 % and 14.58 %) and MMK (19.71 % and 22.40 %) significantly reduced EB dye leakage (p < 0.05). Both formulations, HK and MMK considerably (p < 0.05) decreased plasma histamine (29.62 % and 25.37 % respectively) in mice and eosinophilic count (11.56 % and 9.94 % respectively) and sneeze rate (42.58 % and 29.03 % respectively) in guinea pigs. In membrane stability experiment, HK and MMK reduced RBC lysis. Both HK and MMK raw/dialysate blocked CHO cell cytosolic Ca2+ release. HK and MMK activities mimic mast cell stabilization with possible H1 receptor inactivation seen by decreased Ca2+ efflux and thus indicate potential for allergic rhinitis management. The combination of activities is usually related with curative and prophylactic therapy and might lead future clinical trials and therapies.

A Comprehensive Literature Review on Efficient Synthetic Approaches and Polymorphism of Pazopanib (Votrient), a Tyrosine Kinase Inhibitor

Angiogenesis involves the development of new blood vessels from the pre-existing vasculature. In cancer, an inappropriate or pathological angiogenesis reinforces tumor growth by feeding with nutrient and oxygen. Central to the process of angiogenesis is vascular endothelial growth factor (VEGF) and its receptor (VEGFR), as they regulate angiogenesis and vascular permeability. To stop tumor angiogenesis by cutting off the blood supply, a multitude of angiogenesis inhibitors (antiangiogenic agents or anticancer drugs) have been developed. In pursuit of developing an effective angiogenesis inhibitor, a novel pyrimidine derivative, an inhibitor of VEGFR-2 kinase activity later known as “VOTRIENT (Pazopanib)” was developed by GlaxoSmithKline and approved by the FDA in October 2009 for treatment of advanced renal cell cancer. Later, it was also approved by the FDA for the treatment of advanced soft tissue sarcoma in April 2012. In the literature, there are multiple synthetic pathways reported and the present work reviews the literature related to the synthesis of Pazopanib emphasizing applicability at a commercial scale. The main purpose of this review paper is to provide a comprehensive overview of different existing routes of synthesis with relevant comparison, reported polymorphs, and suggesting further development.

Sars-Cov-2 Spike Protein 1 Activates Microvascular Endothelial Cells: Understanding the Implications

The spike protein of SARS-CoV-2, particularly its subunit Spike Protein 1 (S1), has been identified as a crucial component in the pathogenesis of COVID-19. Recent studies have revealed that SARS-CoV-2 Spike Protein 1 has the ability to activate microvascular endothelial cells, which play a vital role in maintaining vascular integrity and regulating inflammatory responses. This activation of microvascular endothelial cells by the spike protein has significant implications for COVID-19 pathogenesis. It can lead to endothelial dysfunction, increased vascular permeability, recruitment of immune cells, and the release of inflammatory molecules, contributing to the systemic inflammatory response observed in severe cases of COVID-19. Furthermore, it can exacerbate tissue damage and contribute to the cytokine storm. Understanding the mechanisms and consequences of SARS-CoV-2 Spike Protein 1-mediated activation of microvascular endothelial cells is crucial for developing targeted therapeutic interventions to mitigate the inflammatory response and improve patient outcomes. This knowledge may also guide the exploration of existing medications to modulate endothelial dysfunction and attenuate the pathogenic effects of spike protein activation. Continued research in this field is warranted to uncover precise mechanisms and develop effective strategies to combat this aspect of the disease.

Primary brain lymphoma and glioblastoma: evaluation of DCE T1 and DSC T2 MRI perfusion findings.

The accurate differentiation of primary central nervous system lymphoma (PCNSL) from glioblastoma multiforme (GBM) is clinically crucial due to the different treatment strategies between them. To define magnetic resonance imaging (MRI) perfusion findings in PCNSL to make a safe distinction from GBM with dynamic contrast-enhanced (DCE) T1 and DSC T2 MRI perfusion findings. This retrospective analysis included 19 patients with histopathologically diagnosed PCNSL and 21 individuals with GBM. DCE T1 vascular permeability perfusion values including K-trans, Ve, Kep, IAUGC, and DSC T2 perfusion values including cerebral blood volume (CBV) and cerebral blood flow (CBF) in axial sections from the pathological lesion and contralateral normal brain parenchyma were measured quantitatively using region of interest analysis. The study observed no statistically significant difference between patients with PCNSL (T/B cell) and GBM in the median values of DCE T1 perfusion ratios (P > 0.05). Nevertheless, the DSC T2 perfusion ratios showed a substantial distinction between the two groups. In contrast to patients with PCNSL (1.185 vs. 1.224, respectively), those with GBM had higher median levels of r-CBV and r-CBF (2.898 vs. 2.467, respectively; P 0.01). A cutoff value of ≤1.473 for r-CBV (Lesion/N) and ≤1.6005 for r-CBF (Lesion/N) was found to estimate the positivity of PCNSL. DSC T2 MRI perfusion values showed lower r-CBV and r-CBF values in PCNSL patients compared to GBM patients. According to the findings, r-CBV and r-CBF are the most accurate MRI perfusion parameters for distinguishing between PCSNL and GBM.

Human atherosclerotic plaque transcriptomics reveals endothelial beta-2 spectrin as a potential regulator a leaky plaque microvasculature phenotype

The presence of atherosclerotic plaque vessels is a critical factor in plaque destabilization. This may be attributable to the leaky phenotype of these microvessels, although direct proof for this notion is lacking. In this study, we investigated molecular and cellular patterns of stable and hemorrhaged human plaque to identify novel drivers of intraplaque vessel dysfunction. From transcriptome data of a human atherosclerotic lesion cohort, we reconstructed a co-expression network, identifying a gene module strongly and selectively correlated with both plaque microvascular density and inflammation. Spectrin Beta Non-Erythrocytic 1 (sptbn1) was identified as one of the central hubs of this module (along with zeb1 and dock1) and was selected for further study based on its predominant endothelial expression. Silencing of sptbn1 enhanced leukocyte transmigration and vascular permeability in vitro, characterized by an increased number of focal adhesions and reduced junctional VE-cadherin. In vivo, sptbn1 knockdown in zebrafish impaired the development of the caudal vein plexus. Mechanistically, increased substrate stiffness was associated with sptbn1 downregulation in endothelial cells in vitro and in human vessels. Plaque SPTBN1 mRNA and protein expression were found to correlate with an enhanced presence of intraplaque hemorrhage and future cardiovascular disease (CVD) events during follow-up. In conclusion, we identify SPTBN1 as a central hub gene in a gene program correlating with plaque vascularisation. SPTBN1 was regulated by substrate stiffness in vitro while silencing blocked vascular development in vivo, and compromised barrier function in vitro. Together, SPTBN1 is identified as a new potential regulator of the leaky phenotype of atherosclerotic plaque microvessels.

Photobiomodulation Inhibits Ischemia-Induced Brain Endothelial Senescence via Endothelial Nitric Oxide Synthase.

Recent research suggests that photobiomodulation therapy (PBMT) positively impacts the vascular function associated with various cerebrovascular diseases. Nevertheless, the specific mechanisms by which PBMT improves vascular function remain ambiguous. Since endothelial nitric oxide synthase (eNOS) is crucial in regulating vascular function following cerebral ischemia, we investigated whether eNOS is a key element controlling cerebrovascular function and the senescence of vascular endothelial cells following PBMT treatment. Both rat photothrombotic (PT) stroke and in vitro oxygen-glucose deprivation (OGD)-induced vascular endothelial injury models were utilized. We demonstrated that treatment with PBMT (808 nm, 350 mW/cm2, 2 min/day) for 7 days significantly reduced PT-stroke-induced vascular permeability. Additionally, PBMT inhibited the levels of endothelial senescence markers (senescence green and p21) and antiangiogenic factor (endostatin), while increasing the phospho-eNOS (Ser1177) in the peri-infarct region following PT stroke. In vitro study further indicated that OGD increased p21, endostatin, and DNA damage (γH2AX) levels in the brain endothelial cell line, but they were reversed by PBMT. Intriguingly, the beneficial effects of PBMT were attenuated by a NOS inhibitor. In summary, these findings provide novel insights into the role of eNOS in PBMT-mediated protection against cerebrovascular senescence and endothelial dysfunction following ischemia. The use of PBMT as a therapeutic is a promising strategy to improve endothelial function in cerebrovascular disease.

A Focus on the Pathophysiology of Adrenomedullin Expression: Endothelitis and Organ Damage in Severe Viral and Bacterial Infections.

Adrenomedullin (ADM) is a peptide hormone produced primarily in the adrenal glands, playing a crucial role in various physiological processes. As well as improving vascular integrity and decreasing vascular permeability, ADM acts as a vasodilator, positive inotrope, diuretic, natriuretic and bronchodilator, antagonizing angiotensin II by inhibiting aldosterone secretion. ADM also has antihypertrophic, anti-apoptotic, antifibrotic, antioxidant, angiogenic and immunoregulatory effects and antimicrobial properties. ADM expression is upregulated by hypoxia, inflammation-inducing cytokines, viral or bacterial substances, strength of shear stress, and leakage of blood vessels. These pathological conditions are established during systemic inflammation that can result from infections, surgery, trauma/accidents or burns. The ability to rapidly identify infections and the prognostic, predictive power makes it a valuable tool in severe viral and bacterial infections burdened by high incidence and mortality. This review sheds light on the pathophysiological processes that in severe viral or bacterial infections cause endothelitis up to the development of organ damage, the resulting increase in ADM levels dosed through its more stable peptide mid-regional proadrenomedullin (MR-proADM), the most significant studies that attest to its diagnostic and prognostic accuracy in highlighting the severity of viral or bacterial infections and appropriate therapeutic insights.

Risk Factors for Post-Colorectal Endoscopic Submucosal Dissection Bleeding and Efficacy of Carbazochrome Sodium Sulfonate: A Multicenter Retrospective Cohort Study

Introduction: Carbazochrome sodium sulfonate (CSS) is a hemostatic agent that reduces capillary permeability and enhances capillary resistance. However, its specific effects on colorectal endoscopic submucosal dissection (ESD) outcomes remain uncertain. This study aimed to assess the risk factors for post-ESD bleeding and the effect of CSS on colorectal ESD outcomes. Methods: First, we retrospectively analyzed the risk factors for post-ESD bleeding using data from 1,315 lesions in 1,223 patients who underwent ESD for superficial colorectal neoplasms at eight institutions. Second, patients were divided into CSS and non-CSS groups using propensity score matching, and their outcomes from colorectal ESD were analyzed. Results: The risk factors for post-colorectal ESD bleeding were identified as age of ≥70 years, tumor located in the rectum, tumor size of ≥40 mm, and post-ESD defect unclosure in both univariate and multivariate analyses. The CSS and non-CSS groups each consisted of 423 lesions after propensity score matching. The post-colorectal ESD bleeding rate was 3.5% (15/423) and 3.3% (14/423) in the CSS and non-CSS groups, respectively, indicating no significant differences. Among patients with the high-risk factors for post-ESD bleeding, the administration of CSS also did not demonstrate a significant reduction in the post-ESD bleeding rate compared to the non-CSS group. Conclusion: CSS administration is ineffective in preventing post-colorectal ESD bleeding in both the general population and individuals at a high risk for such bleeding. Our results indicate the necessity to reconsider the application of CSS for preventing post-colorectal ESD bleeding.