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A key feature distinguishing high-grade glioma (HG) from low-grade glioma (LG) is the extensive neovascularization and endothelial hyperproliferation. Prior work has shown that tumor-associated vasculature from HG is molecularly and functionally distinct from normal brain vasculature and expresses higher levels of protumorigenic factors that promote glioma growth and progression. However, it remains unclear whether vessels from LG also express protumorigenic factors, and to what extent they functionally contribute to glioma growth. Here, we profile the transcriptomes of glioma-associated vascular cells (GVC) from IDH-mutant (mIDH) LG and IDH-wild-type (wIDH) HG and show that they exhibit significant molecular and functional differences. LG-GVC show enrichment of extracellular matrix-related gene sets and sensitivity to antiangiogenic drugs, whereas HG-GVC display an increase in immune response-related gene sets and antiangiogenic resistance. Strikingly, conditioned media from LG-GVC inhibits the growth of wIDH glioblastoma cells, whereas HG-GVC promotes growth. In vivo cotransplantation of LG-GVC with tumor cells reduces growth, whereas HG-GVC enhances tumor growth in orthotopic xenografts. We identify ASPORIN (ASPN), a small leucine-rich repeat proteoglycan, highly enriched in LG-GVC as a growth suppressor of wIDH glioblastoma cells in vitro and in vivo. Together, these findings indicate that GVC from LG and HG are molecularly and functionally distinct and differentially regulate tumor growth. Implications: This study demonstrated that vascular cells from IDH-mutant LG and IDH-wild-type HG exhibit distinct molecular signatures and have differential effects on tumor growth via regulation of ASPN-TGFβ1-GPM6A signaling.

Glioblastoma is a highly aggressive neoplasm and the most common primary malignant brain tumor. Endothelial tissue plays a critical role in glioblastoma growth and progression, facilitating angiogenesis, cellular communication, and tumorigenesis. In this review, we present an up-to-date and comprehensive summary of the role of endothelial cells in glioblastomas, along with an overview of recent developments in glioblastoma therapies and tumor endothelial marker identification.

Neural progenitor cells within the cerebral cortex undergo a characteristic switch between symmetric self-renewing cell divisions early in development and asymmetric neurogenic divisions later. Yet, the mechanisms controlling this transition remain unclear. Previous work has shown that early but not late neural progenitor cells (NPCs) endogenously express the autism-linked transcription factor Foxp1, and both loss and gain of Foxp1 function can alter NPC activity and fate choices. Here, we show that premature loss of Foxp1 upregulates transcriptional programs regulating angiogenesis, glycolysis, and cellular responses to hypoxia. These changes coincide with a premature destabilization of HIF-1α, an elevation in HIF-1α target genes, including Vegfa in NPCs, and precocious vascular network development. In vitro experiments demonstrate that stabilization of HIF-1α in Foxp1-deficient NPCs rescues the premature differentiation phenotype and restores NPC maintenance. Our data indicate that the endogenous decline in Foxp1 expression activates the HIF-1α transcriptional program leading to changes in the tissue environment adjacent to NPCs, which, in turn, might alter their self-renewal and neurogenic capacities.

BACKGROUND: Loss of AZGP1 expression is a biomarker associated with progression to castration resistance, development of metastasis, and poor disease-specific survival in prostate cancer. However, high expression of AZGP1 cells in prostate cancer has been reported to increase proliferation and invasion. The exact role of AZGP1 in prostate cancer progression remains elusive. METHOD: AZGP1 knockout and overexpressing prostate cancer cells were generated using a lentiviral system. The effects of AZGP1 under- or over-expression in prostate cancer cells were evaluated by in vitro cell proliferation, migration, and invasion assays. Heterozygous AZGP1± mice were obtained from European Mouse Mutant Archive (EMMA), and prostate tissues from homozygous knockout male mice were collected at 2, 6 and 10 months for histological analysis. In vivo xenografts generated from AZGP1 under- or over-expressing prostate cancer cells were used to determine the role of AZGP1 in prostate cancer tumor growth, and subsequent proteomics analysis was conducted to elucidate the mechanisms of AZGP1 action in prostate cancer progression. AZGP1 expression and microvessel density were measured in human prostate cancer samples on a tissue microarray of 215 independent patient samples. RESULT: Neither the knockout nor overexpression of AZGP1 exhibited significant effects on prostate cancer cell proliferation, clonal growth, migration, or invasion in vitro. The prostates of AZGP1-/- mice initially appeared to have grossly normal morphology; however, we observed fibrosis in the periglandular stroma and higher blood vessel density in the mouse prostate by 6 months. In PC3 and DU145 mouse xenografts, over-expression of AZGP1 did not affect tumor growth. Instead, these tumors displayed decreased microvessel density compared to xenografts derived from PC3 and DU145 control cells, suggesting that AZGP1 functions to inhibit angiogenesis in prostate cancer. Proteomics profiling further indicated that, compared to control xenografts, AZGP1 overexpressing PC3 xenografts are enriched with angiogenesis pathway proteins, including YWHAZ, EPHA2, SERPINE1, and PDCD6, MMP9, GPX1, HSPB1, COL18A1, RNH1, and ANXA1. In vitro functional studies show that AZGP1 inhibits human umbilical vein endothelial cell proliferation, migration, tubular formation and branching. Additionally, tumor microarray analysis shows that AZGP1 expression is negatively correlated with blood vessel density in human prostate cancer tissues. CONCLUSION: AZGP1 is a negative regulator of angiogenesis, such that loss of AZGP1 promotes angiogenesis in prostate cancer. AZGP1 likely exerts heterotypical effects on cells in the tumor microenvironment, such as stromal and endothelial cells. This study sheds light on the anti-angiogenic characteristics of AZGP1 in the prostate and provides a rationale to target AZGP1 to inhibit prostate cancer progression.

BACKGROUND: Elephant seals exhibit extreme hypoxemic tolerance derived from repetitive hypoxia/reoxygenation episodes they experience during diving bouts. Real-time assessment of the molecular changes underlying protection against hypoxic injury in seals remains restricted by their at-sea inaccessibility. Hence, we developed a proliferative arterial endothelial cell culture model from elephant seals and used RNA-seq, functional assays, and confocal microscopy to assess the molecular response to prolonged hypoxia. RESULTS: Seal and human endothelial cells exposed to 1% O2 for up to 6 h respond differently to acute and prolonged hypoxia. Seal cells decouple stabilization of the hypoxia-sensitive transcriptional regulator HIF-1α from angiogenic signaling. Rapid upregulation of genes involved in glutathione (GSH) metabolism supports the maintenance of GSH pools, and intracellular succinate increases in seal but not human cells. High maximal and spare respiratory capacity in seal cells after hypoxia exposure occurs in concert with increasing mitochondrial branch length and independent from major changes in extracellular acidification rate, suggesting that seal cells recover oxidative metabolism without significant glycolytic dependency after hypoxia exposure. CONCLUSIONS: We found that the glutathione antioxidant system is upregulated in seal endothelial cells during hypoxia, while this system remains static in comparable human cells. Furthermore, we found that in contrast to human cells, hypoxia exposure rapidly activates HIF-1 in seal cells, but this response is decoupled from the canonical angiogenesis pathway. These results highlight the unique mechanisms that confer extraordinary tolerance to limited oxygen availability in a champion diving mammal.

• CircRNA_0003307 enhanced angiogenesis, invasion, and migration in BMECs under OGD. • CircRNA_0003307 acts as a sponge for miRNA-191-5p, preventing its binding to CDK6. • CircRNA_0003307 enhanced BMEC angiogenesis by targeting the miR-191-5p/CDK6. • CircRNA_0003307 ameliorated cerebral injury in the I/R-injured mice. The role of miR-191-5p in cerebral ischemia–reperfusion (I/R) injury has been established, with its expression in endothelial cells demonstrating anti-angiogenic effects. A potential circular RNA, circRNA_0003307, has been identified through bioinformatics analysis as a candidate for interaction with miR-191-5p, yet its functional significance in brain I/R injury remains unexplored. We aimed to investigate whether circRNA_0003307 regulates brain microvascular endothelial cell (BMEC) vascular tube formation, invasion, and migration by regulating the miR-191-5p cascade. Mouse BMECs (bEnd.3) were cultured and exposed to oxygen-glucose deprivation (OGD). The effects of circRNA_0003307 on vessel-like tube formation and cellular migration were examined. In addition, we investigated the protective effects of circRNA_0003307 on I/R injury in mice. The results showed the level of circRNA_0003307 was concentration-dependently increased in OGD-induced bEnd.3 cells. ODG-induction enhanced angiogenesis, migration, and invasion of bEnd.3 cells, which were further promoted by the transfection of pcDNA-0003307. Silencing circRNA_0003307 expression showed the opposite results. The dual luciferase assay demonstrated miRNA-191-5p interacted with circRNA_00033073′ UTR, and miRNA-191-5p could bind with CDK6. Meanwhile, circRNA_0003307 promoted the expression of CDK6 by sponging miRNA-191-5p. The overexpression of circRNA_0003307 activated the angiogenesis, migration, and invasion of OGD-induced bEnd.3 cells, which were hindered by miRNA-191-5p mimic or siRNA-CDK6. Thus, circRNA_0003307 promoted ODG-induced angiogenesis, migration, and invasion of bEnd.3 cells by targeting miR-191-5p/CDK6 axis. In vivo, circRNA_0003307 had protective effects on brain I/R injury, including neuroprotection, anti-apoptosis and angiogenesis. CircRNA_0003307 may be a promising therapeutic target for the treatment of cerebral I/R injury. [ABSTRACT FROM AUTHOR]

Purpose: Ischemic retinopathy is the major cause of vision-threatening conditions. Inflammation plays an important role in the pathogenesis of ischemic retinopathy. Formyl peptide receptor 1 (FPR1) has been reported to be implicated in the regulation of inflammatory disorders. However, the role of FPR1 in the progression of ischemic retinal injury has not been fully explained. Methods: The activation of FPR1 was measured by real-time PCR and western blotting in the retina of OIR. The effect of FPR1 on the expression of inflammatory cytokines and relevant pro-angiogenic factors was assessed between wild-type and FPR1-deficiency OIR mice. The impact of FPR1 on retinal angiogenesis was evaluated through quantifying retinal vaso-obliteration and neovascularization between FPR1+/+ and FPR1–/– OIR mice. At last, the neuronal effect of FPR1 on the ischemic retina was investigated by ERG between wild-type and FPR1-deficient OIR mice. Results: The expression of FPR1 significantly increased in the retina of OIR. Furthermore, FPR1 deficiency downregulated pro-inflammatory and pro-angiogenic factors. Ablation of FPR1 suppressed the retinal pathological neovascularization and promoted reparative revascularization, ultimately improving retinal neural function after ischemic injury. Conclusion: In ischemic retinopathy, FPR1 aggravates inflammation and inhibits reparative angiogenesis to exacerbate neuronal dysfunction. [ABSTRACT FROM AUTHOR]

Angiogenesis is crucial for successful bone defect repair. Co‐transplanting Bone Marrow Stromal Cells (BMSCs) and Endothelial Cells (ECs) has shown promise for vascular augmentation, but it face challenges in hostile tissue microenvironments, including poor cell survival and limited efficacy. In this study, the mitochondria of human BMSCs are isolated and transplanted to BMSCs from the same batch and passage number (BMSCsmito). The transplanted mitochondria significantly boosted the ability of BMSCsmito‐ECs to promote angiogenesis, as assessed by in vitro tube formation and spheroid sprouting assays, as well as in vivo transplantation experiments in balb/c mouse and SD rat models. The Dll4‐Notch1 signaling pathway is found to play a key role in BMSCsmito‐induced endothelial tube formation. Co‐transplanting BMSCsmito with ECs in a rat cranial bone defect significantly improves functional vascular network formation, and improve bone repair outcomes. These findings thus highlight that mitochondrial transplantation, by acting through the DLL4‐Notch1 signaling pathway, represents a promising therapeutic strategy for enhancing angiogenesis and improving bone repair. Hence, mitochondrial transplantation to BMSCS as a therapeutic approach for promoting angiogenesis offers valuable insights and holds much promise for innovative regenerative medicine therapies. [ABSTRACT FROM AUTHOR]

Background and Purpose Experimental Approach Key Results Conclusion and Implications Angiogenesis is a pathological component of neovascular age‐related macular degeneration. Current therapies, although successful, are prone to high levels of patient non‐response and a loss of efficacy over time, indicating the need to explore other therapeutic avenues. We have shown that an interaction between syndecan‐2 and the tyrosine phosphatase receptor CD148 (RTP Type J) results in the ablation of angiogenesis. Here we exploit this pathway to develop a peptide activator of CD148 as a therapy for neovascular age‐related macular degeneration.We tested a peptide (QM107) derived from syndecan‐2 in a variety of angiogenesis models and a pre‐clinical model of neovascular age‐related macular degeneration. We assessed the toxicological and inflammatory profiles of QM107 and its stability in vitreous humour.QM107 inhibits angiogenesis in ex vivo sprouting assays and disrupts endothelial microcapillary formation via inhibition of cell migration. QM107 acts through CD148, leading to changes in GSK3A phosphorylation and β1 integrin activation. QM107 elicits a negligible inflammatory response and exhibits limited toxicity in cultured cells, and is stable in vitreous humour. Finally, we show proof of concept that QM107 blocks angiogenesis in vivo using a model of neovascular age‐related macular degeneration.We have developed a CD148 activating peptide which shows promise in inhibiting angiogenesis in models of neovascular age‐related macular degeneration. This treatment could either represent an alternative or augment existing therapies, and owing to its distinct mode of action be used in patients who do not respond to existing treatments. [ABSTRACT FROM AUTHOR]

The growth of new blood vessels through angiogenesis is a highly coordinated process, which is initiated by chemokine gradients that activate endothelial cells within a perfused parent vessel to sprout into the surrounding 3D tissue matrix. While both biochemical signals from pro-angiogenic factors, as well as mechanical cues originating from luminal fluid flow that exerts shear stress on the vessel wall, have individually been identified as major regulators of endothelial cell sprouting, it remains unclear whether and how both types of cues synergize. To fill this knowledge gap, here, we created a 3D biomimetic model of chemokine gradient-driven angiogenic sprouting, in which a micromolded tube inside a hydrogel matrix is seeded with endothelial cells and connected to a perfusion system to control fluid flow rates and resulting shear forces on the vessel wall. To allow for the formation of chemokine gradients despite the presence of luminal flow, a nanoporous synthetic hydrogel that supports angiogenesis but limits the interstitial flow proved crucial. Using this system, we find that luminal flow and resulting shear stress is a major regulator of the speed and morphogenesis of angiogenic sprouting, whose action is mediated through changes in vascular permeability. [ABSTRACT FROM AUTHOR]

Background: DNA methylation profiling may provide a more accurate measure of the smoking status than self-report and may be useful in guiding clinical interventions and forensic investigations. In the current study, blood DNA methylation profiles of nearly 800 Polish individuals were assayed using Illuminia EPIC and the inference of smoking from epigenetic data was explored. In addition, we focused on the role of the AHRR gene as a top marker for smoking and investigated its responsiveness to other lifestyle behaviors. Results: We found > 450 significant CpGs associated with cigarette consumption, and overrepresented in various biological functions including cell communication, response to stress, blood vessel development, cell death, and atherosclerosis. The model consisting of cg05575921 in AHRR (p = 4.5 × 10–32) and three additional CpGs (cg09594361, cg21322436 in CNTNAP2 and cg09842685) was able to predict smoking status with a high accuracy of AUC = 0.8 in the test set. Importantly, a gradual increase in the probability of smoking was observed, starting from occasional smokers to regular heavy smokers. Furthermore, former smokers displayed the intermediate DNA methylation profiles compared to current and never smokers, and thus our results indicate the potential reversibility of DNA methylation after smoking cessation. The AHRR played a key role in a predictive analysis, explaining 21.5% of the variation in smoking. In addition, the AHRR methylation was analyzed for association with other modifiable lifestyle factors, and showed significance for sleep and physical activity. We also showed that the epigenetic score for smoking was significantly correlated with most of the epigenetic clocks tested, except for two first-generation clocks. Conclusions: Our study suggests that a more rapid return to never-smoker methylation levels after smoking cessation may be achievable in people who change their lifestyle in terms of physical activity and sleep duration. As cigarette smoking has been implicated in the literature as a leading cause of epigenetic aging and AHRR appears to be modifiable by multiple exogenous factors, it emerges as a promising target for intervention and investment. [ABSTRACT FROM AUTHOR]

Background: Legg-Calvé-Perthes disease (LCPD) commonly occurs among adolescents, threatening their health. However, the potential mechanism underlying LCPD remains unclear. miR-214-3p is shown as a critical role in LCPD development with unspecified upstream regulators. Methods: Levels of miR-214-3p and circCDR1as in healthy controls and LCPD patients were determined by qRT-PCR. The role of circCDR1as/miR-214-3p axis in LCPD was determined by testing the cell viability and apoptosis in TC28 cells and primary chondrocytes. Regulation between circCDR1as and miR-214-3p was examined by RIP and ChIP assays. The inflammatory response and angiogenesis were evaluated by M2 macrophage polarization and HUVECs tumor formation. Results: circCDR1as was overexpressed in LCPD patients with a negative correlation with miR-214-3p. Inhibition of circCDR1as alleviated the cell viability and apoptosis of DEX-treated chondrocytes, stimulated M2 macrophage polarization and angiogenesis. miR-214-3p was proved as a downstream effector to participate in circCDR1as mediated actions. circCDR1as recruited PRC2 complex to epigenetically suppress miR-214-3p. Conclusion: Our study illustrated the role and mechanism of circCDR1as in LCPD development by targeting miR-214-3p, highlighting its potential in the therapy for LCPD. [ABSTRACT FROM AUTHOR]

ABSTRACT Due to its intricate molecular and structural characteristics, vascular endothelial growth factor receptor 2 (VEGFR‐2) is essential for the development of new blood vessels in various pathological processes and conditions, especially in cancers. VEGFR‐2 inhibitors have demonstrated significant anticancer effects by blocking many signaling pathways linked to tumor growth, metastasis, and angiogenesis. Several small compounds, including the well‐tolerated sunitinib and sorafenib, have been approved as VEGFR‐2 inhibitors. However, the widespread side effects linked to these VEGFR‐2 inhibitors—hypertension, epistaxis, proteinuria, and upper respiratory infection—motivate researchers to search for new VEGFR‐2 inhibitors with better pharmacokinetic profiles. The key molecular interactions required for the interaction of the small molecules with the protein target to produce the desired pharmacological effects are identified using computer‐aided drug design (CADD) methods such as pharmacophore and QSAR modeling, structure‐based virtual screening, molecular docking, molecular dynamics (MD) simulation coupled with MM/PB(GB)SA, and other computational strategies. This review discusses the applications of these methods for VEGFR‐2 inhibitor design. Future VEGFR‐2 inhibitor designs may be influenced by this review, which focuses on the current trends of using multiple screening layers to design better inhibitors. [ABSTRACT FROM AUTHOR]

Endothelial cells are key players in the cardiovascular system. Among other things, they are responsible for sprouting angiogenesis, the process of new blood vessel formation essential for both health and disease. Endothelial cells are strongly regulated by the juxtacrine signaling pathway Notch. Recent studies have shown that both Notch and angiogenesis are influenced by extracellular matrix stiffness; however, the underlying mechanisms are poorly understood. Here, we addressed this challenge by combining computational models of Notch signaling and YAP/TAZ, stiffness- and cytoskeleton-regulated mechanotransducers whose activity inhibits both Dll4 (Notch ligand) and LFng (Notch-Dll4 binding modulator). Our simulations successfully mimicked previous experiments, indicating that this YAP/TAZ-Notch crosstalk elucidates the Notch and angiogenesis mechanoresponse to stiffness. Additional simulations also identified possible strategies to control Notch activity and sprouting angiogenesis via cytoskeletal manipulations or spatial patterns of alternating stiffnesses. Our study thus inspires new experimental avenues and provides a promising modeling framework for further investigations into the role of Notch, YAP/TAZ, and mechanics in determining endothelial cell behavior during angiogenesis and similar processes. [ABSTRACT FROM AUTHOR]

Background: to analyze, at one year, the efficacy and safety of treat-and-extend (T&E) intravitreal (IV) Brolucizumab in patients affected by macular neovascularization (MNV). Both naïve and previously treated (i.e., switched) patients were included, and the data from the two groups were compared. Methods: anatomical (i.e., central subfoveal thickness, CST; presence of fluid), functional (i.e., best corrected visual acuity, BCVA) and treatment-related (i.e., number of IV injections within the study period; number of patients reaching a 12-weeks interval between treatments) data from 41 eyes of 41 subjects (20 naïve and 21 switched) were analyzed. Patients were treated with 3 monthly IV injections followed by a T&E regimen based on a disease activity assessment performed at each scheduled IV treatment. Results: significant CST reduction (from 412.1 ± 115.8 to 273.2 ± 61.6; p < 0.05) and BCVA (mean; p) improvement were observed in the naïve group, while in the switched cohort, both parameters were almost stable. In the naïve and switched groups, 55% and 33.5% of patients, respectively, reached a 12-week IV interval at one year, with a mean of 6.55 ± 1 and 7.43 ± 0.68 IV treatments, respectively. One patient with mild anterior uveitis without sequelae was recorded. Conclusion: In patients with MNV, IV Brolucizumab injections following a T&E regimen demonstrated great efficacy and a good safety profile, with greater anatomical and functional results in naïve patients. Trial registration: This study was approved by the Local Ethics Committee (protocol number 155/2020, general registry number n°11486, InterHospital Ethics Committee, San Luigi Gonzaga Hospital, Orbassano, Italy). [ABSTRACT FROM AUTHOR]

Purpose • Angiogenesis, the formation of new blood vessels, plays a crucial role in tumor growth and metastasis. Understanding the vascular characteristics of colorectal cancer through preoperative computed tomography (CT) perfusion parameters can provide valuable insights into the tumor’s aggressiveness and potential for spread. Additionally, exploring the correlation between these parameters and serum tumor marker levels may offer a comprehensive perspective on the disease’s biological behavior. Methods • In this retrospective study, we investigated 42 colorectal cancer patients. Based on microvascular density (MVD) measured by immunohistochemistry (IHC), participants were categorized into either a high-density group (n = 24) with MVD ≥ 35/field of view or a low-density group (n = 18) with MVD < 35/field of view. Additionally, a control group comprised 25 patients with pathologically confirmed benign colorectal lesions. This study design allowed us to assess the correlation between MVD and colorectal cancer, differentiating between high and low microvascular density groups, while also comparing results to a control group for comprehensive analysis. Results • Colorectal cancer was associated with significantly higher levels of blood volume (BV; high-density group: 7.65±1.36 mL/100g; low-density group: 6.73±1.29 mL/100g), blood flow (BF; high-density group: 67.33±12.16 ml/(100g·min); low-density group: 52.84±11.43 ml/ (100g·min)), permeability surface (PS; high-density group: 35.19±6.32 ml/(100g·min); low-density group: 22.27±4.85 ml/(100g·min)), serum glycoprotein antigen 19-9 (CA19-9; high-density group: 45.38±5.41 g/ ml); low-density group: 23.43±3.59 g/ml), glycoprotein antigen 125 (CA125; high-density group: 27.56±3.73 g/ml); low-density group: 12.63±2.59 g/ml), and carcinoembryonic antigen (CEA; high-density group: 17.87±3.12 g/ml); low-density group: 8.51±2.87 g/ml) versus benign colorectal lesions, with more significant changes observed in the high-density group versus the low-density group (P ≤ .001). The three groups showed similar mean transit time (MTT). The AUCs under the ROC curves for BV, BF, PS, and TTP were 0.901, 0.898, 0.963, and 0.983, respectively. Pearson correlation analysis showed a positive correlation of patients’ serum CA19-9 with BV, BF, and PS., Serum CA125 and CEA were positively correlated with BF and PS, and the above indicators were negatively correlated with TTP. Conclusions • In conclusion, our study highlights the potential of preoperative CT perfusion imaging as a valuable tool for evaluating angiogenesis in colorectal cancer and its correlation with serum tumor markers. The identified associations open avenues for further research to delve into specific aspects of angiogenesis and tumor markers. Future investigations could focus on elucidating the molecular mechanisms underlying the observed correlations, potentially identifying novel therapeutic targets. Additionally, exploring the dynamic changes in angiogenesis and tumor markers during different stages of colorectal cancer progression may provide a more comprehensive understanding. Moreover, assessing the prognostic value of these imaging and biomarker correlations in larger, diverse patient cohorts could enhance their clinical utility. Our findings lay the groundwork for these future research directions, emphasizing the need for continued exploration to advance our knowledge and improve clinical strategies for colorectal cancer management. [ABSTRACT FROM AUTHOR]

Hepatocellular adenomas (HAs) are tumors that can develop under different conditions, including in patients harboring a germline mutation in HNF1A. However, little is known about the pathogenesis of such disease. This work aims to better define what mechanisms lie under the development of this condition. Six HAs were sampled from the liver of a 17-year-old male affected by diabetes and multiple hepatic adenomatosis harboring the heterozygous pathogenic germline variant c.815G>A, p.(Arg272His) in HNF1A, which has a dominant negative effect. All HAs were molecularly characterized. Four of them were shown to harbor a second somatic HNF1A variant and one had a mutation in the ARID1A gene, while no additional somatic changes were found in the remaining HA and normal parenchyma. A transcriptomic profile of the same HA samples was also performed. HNF1A biallelic mutations were associated with the up-regulation of several pathways including the tricarboxylic acid cycle, the metabolism of fatty acids, and mTOR signaling while angiogenesis, endothelial and vascular proliferation, cell migration/adhesion, and immune response were down-regulated. Contrariwise, in the tumor harboring the ARID1A variant, angiogenesis was up-modulated while fatty acid metabolism was down-modulated. Histological analyses confirmed the molecular data. Independently of the second mutation, energetic processes and cholesterol metabolism were up-modulated, while the immune response was down-modulated. This work provides a complete molecular signature of HNF1A-associated HAs, analyzing the association between specific HNF1A variants and the development of HA while identifying potential new therapeutic targets for non-surgical treatment. [ABSTRACT FROM AUTHOR]

Aim: Endometriosis is a complex, multifactorial disease. Recent advances in molecular biology underscore that somatic mutations within the epithelial component of the normal endometrium, alongside aberrant epigenetic alterations within endometrial stromal cells, may serve as stimulators for the proliferation of endometriotic tissue within the peritoneal cavity. Nevertheless, pivotal inquiries persist: the deterministic factors driving endometriosis development in certain women while sparing others, notwithstanding comparable experiences of retrograde menstruation. Within this review, we endeavor to synopsize the current understanding of diverse pathophysiologic mechanisms underlying the initiation and progression of endometriosis and delineate avenues for future research. Methods: A literature search without time restriction was conducted utilizing PubMed and Google Scholar. Results: Given that aberrant clonal expansion stemming from cancer‐associated mutations is common in normal endometrial tissue, only endometrial cells harboring mutations imparting proliferative advantages may be selected for survival outside the uterus. Endometriotic cells capable of engendering metabolic plasticity and modulating mitochondrial dynamics, thereby orchestrating responses to hypoxia, oxidative stress, inflammation, hormonal stimuli, and immune surveillance, and adeptly acclimating to their harsh surroundings, stand a chance at viability. Conclusion: The genesis of endometriosis appears to reflect the evolutionary principles of mutation, selection, clonal expansion, and adaptation to the environment. [ABSTRACT FROM AUTHOR]

Stem cells-derived extracellular vesicles (SC-EVs) have emerged as promising therapeutic agents for wound repair, recapitulating the biological effects of parent cells while mitigating immunogenic and tumorigenic risks. These EVs orchestrate wound healing processes, notably through modulating angiogenesis—a critical event in tissue revascularization and regeneration. This study provides a comprehensive overview of the multifaceted mechanisms underpinning the pro-angiogenic capacity of EVs from various stem cell sources within the wound microenvironment. By elucidating the molecular intricacies governing their angiogenic prowess, we aim to unravel the mechanistic repertoire underlying their remarkable potential to accelerate wound healing. Additionally, methods to enhance the angiogenic effects of SC-EVs, current limitations, and future perspectives are highlighted, emphasizing the significant potential of this rapidly advancing field in revolutionizing wound healing strategies. [ABSTRACT FROM AUTHOR]

Birth rates continue to decline as more women experience fertility issues. Assisted reproductive technologies are available for patients seeking fertility treatment, including cryopreservation techniques. Cryopreservation can be performed on gametes, embryos, or gonadal tissue and can be used for patients who desire to delay in vitro fertilization treatment. This review focuses on ovarian tissue cryopreservation, the freezing of ovarian cortex containing immature follicles. Ovarian tissue cryopreservation is the only available treatment for the restoration of ovarian function in patients who undergo gonadotoxic treatments, and its wide adoption has led to its recent designation as "no longer experimental" by the American Society for Reproductive Medicine. Ovarian tissue cryopreservation and subsequent transplantation can restore native endocrine function and can support the possibility of pregnancy and live birth for the patient. Importantly, there are multiple steps in the procedure that put the ovarian reserve at risk of damage. The graft is highly susceptible to ischemic reperfusion injury and mass primordial follicle growth activation, resulting in a "burnout" phenomenon. In this review, we summarize current efforts to combat the loss of primordial follicles in grafts through improvements in freeze and thaw protocols, transplantation techniques, and pharmacologic adjuvant treatments. We conducted a review of the literature, with emphasis on emergent research in the last 5 years. Regarding freeze and thaw protocols, we discuss the widely accepted slow freezing approach and newer vitrification protocols. Discussion of improved transplantation techniques includes consideration of the transplantation location of the ovarian tissue and the importance of graft sites in promoting neovascularization. Finally, we discuss pharmacologic treatments being studied to improve tissue performance postgraft. Of note, there is significant research into the efficacy of adjuvants used to reduce ischemic injury, improve neovascularization, and inhibit hyperactivation of primordial follicle growth activations. Although the "experimental" label has been removed from ovarian tissue cryopreservation and subsequent transplantation, there is a significant need for further research to better understand sources of ovarian reserve damage to improve outcomes. Future research directions are provided as we consider how to reach the most hopeful results for women globally. [ABSTRACT FROM AUTHOR]

Notch ligands and receptors, including JAG1/2, DLL1/4, and Notch1/3, are enriched on macrophages (MΦs), fibroblast‐like synoviocytes (FLS), and/or endothelial cells in rheumatoid arthritis (RA) compared with normal synovial tissues (ST). Power Doppler ultrasound‐guided ST studies reveal that the Notch family is highly involved in early active RA, especially during neovascularization. In contrast, the Notch family is not implicated during the erosive stage, evidenced by their lack of correlation with radiographic damage in RA ST. Toll‐like receptors and tumor necrosis factor (TNF) are the common inducers of Notch expression in RA MΦs, FLS, and endothelial cells. Among Notch ligands, JAG1 and/or DLL4 are most inducible by inflammatory responses in RA MΦs or endothelial cells and transactivate their receptors on RA FLS. TNF plays a central role on Notch ligands, as anti‐TNF good responders display JAG1/2 and DLL1/4 transcriptional downregulation in RA ST myeloid cells. In in vitro studies, TNF increases Notch3 expression in MΦs, which is further amplified by RA FLS addition. Specific disease‐modifying antirheumatic drugs reduced JAG1 and Notch3 expression in MΦ and RA FLS cocultures. Organoids containing FLS and endothelial cells have increased expression of JAG1 and Notch3. Nonetheless, Methotrexate, interleukin‐6 receptor (IL‐6R) antibodies, and B cell blockers are mostly ineffective at decreasing Notch family expression. NF‐κB, MAPK, and AKT pathways are involved in Notch signaling, whereas JAK/STATs are not. Although Notch blockade has been effective in RA preclinical studies, its small molecule inhibitors have failed in phase I and II studies, suggesting that alternative strategies may be required to intercept their function. [ABSTRACT FROM AUTHOR]

Introduction: This study investigates the early temporal changes in pigment epithelial detachment (PED) morphology following treatment with faricimab in patients with neovascular age-related macular degeneration (nAMD). Utilizing an artificial intelligence (AI)-assisted approach, we provide a detailed quantification and characterization of the dynamics of these morphological changes. Methods: A prospective observational study was conducted on 22 eyes from 22 treatment-naïve patients with nAMD-associated PED (presenting either type 1 or type 3 macular neovascularization). Participants were administered intravitreal faricimab (6 mg) at baseline and at days 30, 60, and 90. Comprehensive ophthalmic evaluations and spectral-domain optical coherence tomography (SD-OCT) imaging were conducted at baseline and at seven additional follow-up visits on days 1, 7, 14, 30, 60, 90, and 120. An AI-based automated segmentation algorithm was utilized to precisely quantify changes in PED volume, alongside intraretinal (IRF) and subretinal fluid (SRF) volumes, at each time point. Results: Treatment with faricimab resulted in a significant reduction in mean PED volume, with an average decrease of 12% at day 1, 29% at day 7, 51% at day 14, 68% at day 30, 72% at day 60, 79% at day 90, and 84% at day 120 (p < 0.0001 for all time points). Similarly rapid and marked reductions were noted in both mean IRF (23.5% at day 1, 90.7% at day 14) and SRF (14.4% at day 1, 91.2% at day 14) volumes. The study also showed a statistically significant improvement in best-corrected visual acuity (BCVA) over the follow-up period, correlating with the reduction in PED volume. Conclusion: Faricimab demonstrates early and significant efficacy in improving PED architecture in patients with nAMD. The rapid morphological improvements observed in this study suggest faricimab may represent a valid therapeutic option for PEDs associated with nAMD. [ABSTRACT FROM AUTHOR]

In advanced hepatocellular carcinoma (HCC) tissues, M2-like tumor-associated macrophages (TAMs) are in the majority and promotes HCC progression. Contrary to the pro-tumor effect of M2-like TAMs, M1-like TAMs account for a small proportion and have anti-tumor effects. Since TAMs can switch from one type to another, reprogramming TAMs may be an important treatment for HCC therapy. However, the mechanisms of phenotypic switch and reprogramming TAMs are still obscure. In this study, we analyzed differential genes in normal macrophages and TAMs, and found that loss of MANF in TAMs accompanied by high levels of downstream genes negatively regulated by MANF. MANF reprogrammed TAMs into M1 phenotype. Meanwhile, loss of MANF promoted HCC progression in HCC patients and mice HCC model, especially tumor neovascularization. Additionally, macrophages with MANF supplement suppressed HCC progression in mice, suggesting MANF supplement in macrophage was an effective treatment for HCC. Mechanistically, MANF enhanced the HSF1–HSP70-1 interaction, restricted HSF1 in the cytoplasm of macrophages, and decreased both mRNA and protein levels of HSP70-1, which in turn led to reprogramming TAMs, and suppressing neovascularization of HCC. Our study contributes to the exploration the mechanism of TAMs reprogramming, which may provide insights for future therapeutic exploitation of HCC neovascularization. MANF enhances the interaction of HSF1 and HSP70-1, which in turn inhibits HSF1 nuclear import and decreases HSP70-1 transcription, leading to the reprogramming of TAMs and further inhibition of HCC neovascularization. [Display omitted] [ABSTRACT FROM AUTHOR]

Skin tissue engineering is undergoing tremendous expansion as a result from clinical needs, mandatory replacement of animal models and development of new technologies. Many approaches have been used to produce vascularized skin substitutes for grafting purposes showing the presence of capillary-like structures but with limited analysis of their in vitro maturation and plasticity. Such knowledge is however important for the development of tissue substitutes with improved implantation success as well as for validation of vascularization in vitro models, including as a readout in pharmacological analyses. For optimal interactions of cells with microenvironment and vasculature, we here used a cell sheet approach consisting in the sole production of matrix by the cells. In this context, we limited the density of endothelial cells seeded for self-assembly and rather relied on the stimulation of angiogenesis for the development of an extensive connected microvascular-like network. After detailed characterization of this network, we challenged its plasticity both during and after establishment of the skin substitute. We show that fine tuning of VEGF concentration and time of application differentially affects formation of capillary-like structures and their perivascular coverage. Furthermore, we performed a deep wound assay that displayed tissue repair and angiogenesis with unique characteristics of the physiological process. These studies demonstrate the importance of cell-derived microenvironment for the establishment of mature yet dynamic vascularized skin models allowing a wide range of pharmacological and basic investigations. The significant advancements in organ-on-chips and tissue engineering call for more relevant models including microvascularization with remodeling potential. While vascularized skin substitutes have been developed for years, focus has primarily been on the impact of microvascularization on implantation rather than on its in vitro characterization. We here developed a cell sheet-based vascularized skin substitute relying on angiogenesis, i.e. growth of vessel-like structures within the 3D model, rather than solely on endothelial cell self-assembly. We then characterized :1/ vascularization after modulation of angiogenic factor VEGF during the substitute construction; -2/ angiogenesis associated to tissue repair after deep mechanical wounding. These studies establish a solid physiologically relevant model for further investigation of skin cell interactions and in vitro wound healing. [Display omitted] [ABSTRACT FROM AUTHOR]

Objective: To study the effect of Shexiang Tongxin Dropping Pill (STDP) on angiogenesis in diabetic cardiomyopathy mice with coronary microcirculation dysfunction (CMD). Methods: According to a random number table, 6 of 36 SPF male C57BL/6 mice were randomly selected as the control group, and the remaining 30 mice were injected with streptozotocin intraperitoneally to replicate the type 1 diabetes model. Mice successfully copied the diabetes model were randomly divided into the model group, STDP low-dose group [15 mg/(kg·d)], medium-dose group [30 mg/(kg·d)], high-dose group [60 mg/(kg·d)], and nicorandil group [15 mg/(kg·d)], 6 in each group. The drug was given by continuous gavage for 12 weeks. The cardiac function of mice in each group was detected at the end of the experiment, and coronary flow reserve (CFR) was detected by chest Doppler technique. Pathological changes of myocardium were observed by hematoxylin-eosin staining, collagen fiber deposition was detected by masson staining, the number of myocardial capillaries was detected by platelet endothelial cell adhesion molecule-1 staining, and the degree of myocardial hypertrophy was detected by wheat germ agglutinin staining. The expression of the vascular endothlial growth factor (VEGF)/endothelial nitric oxide synthase (eNOS) signaling pathway-related proteins in myocardial tissue was detected by Western blot. Results: Compared with the model group, medium- and high-dose STDP significantly increased the left ventricular ejection fraction and left ventricular fraction shortening (P<0.01), obviously repaired the disordered cardiac muscle structure, reduced myocardial fibrosis, reduced myocardial cell area, increased capillary density, and increased CFR level (all P<0.01). Western blot showed that high-dose STDP could significantly increase the expression of VEGF and promote the phosphorylation of vascular endothelial growth factor receptor 2, phosphoinositide 3-kinase, protein kinase B, and eNOS (P<0.05 or P<0.01). Conclusion: STDP has a definite therapeutic effect on diabetic CMD, and its mechanism may be related to promoting angiogenesis through the VEGF/eNOS signaling pathway. [ABSTRACT FROM AUTHOR]

Indirect bypass surgery is an effective treatment for moyamoya disease (MMD), but the success of the surgery depends on the formation of spontaneous collateral vessels, which cannot be accurately predicted before surgery. Developing a prediction nomogram model for neoangiogenesis in patients after indirect revascularization surgery can aid surgeons in identifying suitable candidates for indirect revascularization surgery. This retrospective observational study enrolled patients with MMD who underwent indirect bypass surgery from a multicenter cohort between December 2010 and December 2018. Data including potential clinical and radiological predictors were obtained from hospital records. A nomogram was generated based on a multivariate logistic regression analysis identifying potential predictors of good neoangiogenesis. A total of 263 hemispheres of 241 patients (mean ± SD age 24.38 ± 15.78 years, range 1–61 years) were reviewed, including 168 (63.9%) hemispheres with good postoperative collateral formation and 95 (36.1%) with poor postoperative collateral formation. Based on multivariate analysis, a nomogram was formulated incorporating four predictors, including age at operation, abundance of ICA moyamoya vessels, onset type, and Suzuki stage. The C-index for this nomogram was 0.80. Calibration curve and decision-making analysis validated the fitness and clinical application value of this nomogram. The nomogram developed in this study exhibits high accuracy in predicting good neoangiogenesis after indirect revascularization surgery in MMD patients. This model can be very helpful for clinicians when making decisions about surgical strategies for MMD patients in clinical practice. [ABSTRACT FROM AUTHOR]

Diabetic foot ulcer typically undergoes a delayed wound‐healing process owing to the disordered microenvironment, including persistent inflammation, long‐term hypoxia, and excessive fibrosis, eventually leading to severe disabilities and other poor outcomes. However, current strategies cannot meet the dynamic demands during the wound‐healing process. Herein, a reactive oxygen species (ROS)–responsive oxygen‐generating microneedle platform, consisting of a sericin‐based glucose‐responsive hydrogel loaded with verteporfin, for effective diabetic wound healing is proposed. Under a highly oxidative microenvironment, the functionalized sericin protein depletes overproduced ROS to generate oxygen, which can not only alleviate the hypoxic microenvironment and promote angiogenesis by activating extracellular signal‐regulated kinase and Heme Oxygenase‐1 pathways but also decrease the expression of proinflammatory cytokines. Moreover, the hyperglycaemic condition triggers the gradual dissociation of this microneedle platform and promotes the release of verteporfin to enhance scarless re‐epithelization via inhibiting the yes‐associated protein signal. This versatile sericin microneedle system integrates advantageous features including inflammation alleviation, angiogenesis promotion, and scar inhibition capabilities, accelerates diabetic wound repair in vivo, and offers a novel approach for oxygen self‐supply and wound microenvironment remodeling. [ABSTRACT FROM AUTHOR]

Objective: The aim of this study is to investigate the value of modified parameters derived from dual-phase contrast-enhanced computed tomography (CT) in predicting angiogenesis within pheochromocytoma. Method: A total of 31 patients with pathologically confirmed pheochromocytoma underwent preoperative dual-phase contrast-enhanced CT scanning, wherein modified CT enhancement parameters, namely maximum enhancement difference (∆H) and maximum enhancement velocity (V), were quantified. Subsequently, postoperative specimens were evaluated by pathological section, while microvessel density (MVD) and vascular endothelial growth factor (VEGF) levels were counted. We conducted comparative analyses to assess disparities in maximum enhancement difference and enhancement velocity between groups characterized by high and low VEGF expression. Furthermore, correlations between maximum enhancement difference, enhancement velocity, and MVD were examined, along with an assessment of the association between maximum enhancement difference, VEGF expression, and MVD at the point of maximal enhancement difference occurrence. Results: In the study group, unilateral pheochromocytoma was observed in 31 cases, with 19 cases of arterial phase enhancement and 12 cases displaying venous phase enhancement. The range of maximum enhancement difference (ΔH) spanned from 24 to 102 HU, while the range of maximum enhancement velocity (V) extended from 0.40 HU/s to 4.08 HU/s. Analysis revealed a significant elevation in MVD value within the arterial phase enhancement group compared to the venous phase enhancement group. Additionally, a positive correlation was discerned between the maximum enhancement difference, V, and MVD. Notably, both ∆H and V exhibited statistically significant elevations in the high VEGF expression group relative to the low VEGF expression group. Furthermore, a positive correlation was observed between both ΔH and V and VEGF expression levels. Conclusion: Increased values of ∆H and V are indicative of heightened MVD and VEGF expression. Consequently, the modified parameters derived from dual-phase contrast-enhanced CT scanning serve as predictive markers for angiogenesis in adrenal pheochromocytoma. [ABSTRACT FROM AUTHOR]

ABSTRACT Objective Mathematical Framework Results Conclusion Neovascularization has been extensively studied because of its significant role in both physiological processes and diseases. The significance of vascular microfluidic platforms lies in its essential role in recreating an in vitro environment capable of supporting cellular and tissue systems through the process of neovascularization. Biomechanical properties in a tissue engineered system use fluid flow and transport properties to recapitulate physiological systems. This enables mimicry of organ systems which can further personalized and regenerative medicine. Thus, fluid hemodynamics can be used to study these flow patterns and create a system that mimics real physiological pathways and processes. The establishment of stable flow pathways encourages endothelial cells (ECs) ECs to undergo neovascularization. Specifically, the shear stress applied in capillary beds generates the increased proliferation and differentiation of ECs to build larger microcirculatory beds.Here, we describe a mathematical model that uses branching patterns and vessel morphology to predict hemodynamic parameters in capillary beds.A retinal capillary bed is used as one‐use case of our model to show how the mathematical framework can be used to determine hemodynamic parameters for any microfluidic system.In doing so, this tool can be altered to be used to supplement emerging research areas in neovascularization. [ABSTRACT FROM AUTHOR]

Using bone regeneration scaffolds to repair craniomaxillofacial bone defects is a promising strategy. However, most bone regeneration scaffolds still exist some issues such as a lack of barrier structure, inability to precisely match bone defects, and necessity to incorporate biological components to enhance efficacy. Herein, inspired by a periosteum‐bone complex, a class of multifunctional hierarchical porous poly(lactic‐co‐glycolic acid)/baicalein scaffolds is facilely prepared by the union of personalized negative mold technique and phase separation strategy and demonstrated to precisely fit intricate bone defect cavity. The dense up‐surface of the scaffold can prevent soft tissue cell penetration, while the loose bottom‐surface can promote protein adsorption, cell adhesion, and cell infiltration. The interior macropores of the scaffold and the loaded baicalein can synergistically promote cell differentiation, angiogenesis, and osteogenesis. These findings can open an appealing avenue for the development of personalized multifunctional hierarchical materials for bone repair. [ABSTRACT FROM AUTHOR]

Background: Tongue defects have several etiologies and significantly affect the quality of life. This study was conducted to compare the regenerative potential of erythropoietin (EPO)-loaded hydrogel and adipose derived stem cell (ADSC) secretome on tongue dorsum defects focusing on the role of anti-inflammatory M2 macrophage phenotype. Methods: Rats were subjected to induction of mechanical circular defects on the dorsal surface of the tongue, then divided into three groups; Group I (control): received 0.1 ml phosphate buffered saline, Group II (EPO): received 5000 U/kg EPO-hydrogel, and Group III (ADSC-Secretome): received 0.1 ml ADSC-Secretome. Treatments were injected circumferentially around wound margins after induction. Seven and fourteen days after treatment, specimens were obtained and processed for histological and immunohistochemical staining followed by the relevant histomorphometric and statistical analyses. Results: Seven days after treatment, groups II and III presented defects with some epithelial regeneration at the lateral margins, while the center of the defect showed granulation tissue with much inflammatory cells. The base of the defects showed some muscle fibers and new blood vessels, however group III showed more enhanced neovascularization. Fourteen days after therapeutic intervention, group II defects were completely covered with epithelium showing a thin keratin layer with regular rete pegs interdigitating with the underlying connective tissue papillae, but tongue papillae were not restored. Group III expressed much better healing with developing filiform papillae. The connective tissue showed more vascularity and well-arranged muscle bundles. Both treated groups showed a significant decrease in defect depth and significant increase in anti-inflammatory macrophages compared to the control group at both time intervals, however there was no significant difference between the two treated groups. Conclusion: Both treatments showed promising and comparable results in the treatment of tongue defects reducing inflammation and restoring tongue histological architecture with significant upregulation of M2 macrophage. [ABSTRACT FROM AUTHOR]

Background: Adrenomedullin (AM) is a multifunctional peptide which under basal conditions mainly regulates vasodilation and maintains vascular integrity but is also implicated in the pathogenesis of several malignancies, including multiple myeloma (MM). It has been shown that adrenomedullin is expressed by human myeloma cell lines and that it enhances MM‐driven angiogenesis. However, the clinical impact of AM remains unknown. Materials and Methods: On that basis, we enrolled 32 newly diagnosed multiple myeloma patients (NDMM) and studied the potential of AM as a prognostic biomarker. Results: We report that elevated levels of AM trend with suboptimal treatment response and inferior survival of NDMM patients. [ABSTRACT FROM AUTHOR]

The vascular endothelium, a specialized monolayer of endothelial cells (ECs), is crucial for maintaining vascular homeostasis by controlling the passage of substances and cells. In the tumor microenvironment, Vascular Endothelial Growth Factor A (VEGF-A) drives tumor angiogenesis, leading to endothelial anergy and vascular immunosuppression—a state where ECs resist cytotoxic CD8+ T cell infiltration, hindering immune surveillance. Immunotherapies have shown clinical promise. However, their effectiveness is significantly reduced by tumor EC anergy. Anti-angiogenic treatments aim to normalize tumor vessels and improve immune cell infiltration. Despite their potential, these therapies often cause significant systemic toxicities, necessitating new treatments. The small GTPase Rap1B emerges as a critical regulator of Vascular Endothelial Growth Factor Receptor 2 (VEGFR2) signaling in ECs. Our studies using EC-specific Rap1B knockout mice show that the absence of Rap1B impairs tumor growth, alters vessel morphology, and increases CD8+ T cell infiltration and activation. This indicates that Rap1B mediates VEGF-A's immunosuppressive effects, making it a promising target for overcoming vascular immunosuppression in cancer. Rap1B shares structural and functional similarities with RAS oncogenes. We propose that targeting Rap1B could enhance therapies' efficacy while minimizing adverse effects by reversing endothelial anergy. We briefly discuss strategies successfully developed for targeting RAS as a model for developing anti-Rap1 therapies. [ABSTRACT FROM AUTHOR]

We introduce a multi-species diffuse interface model for tumor growth, characterized by its incorporation of essential features related to chemotaxis, angiogenesis and proliferation mechanisms. We establish the weak well-posedness of the system within an appropriate variational framework, accommodating various choices for the nonlinear potentials. One of the primary novelties of the work lies in the rigorous establishment of the existence of a weak solution through the introduction of delicate approximation schemes. To our knowledge, this represents a novel advancement for both the intricate Cahn–Hilliard–Keller–Segel system and the Keller–Segel subsystem with source terms. Moreover, when specific conditions are met, such as having more regular initial data, a smallness condition on the chemotactic constant with respect to the magnitude of initial conditions and potentially focusing solely on the two-dimensional case, we provide regularity results for the weak solutions. Finally, we derive a continuous dependence estimate, which, in turn, leads to the uniqueness of the smoothed solution as a natural consequence. [ABSTRACT FROM AUTHOR]

The present study aimed to compare the effect of photobiomodulation with different energy densities on the angiogenic differentiation of human periodontal ligament stem cells (hPDLSCs) and stem cells from human exfoliated deciduous teeth (SHED). Photobiomodulation therapy with a 660 nm diode laser (2.4 J/cm2 and 3.9 J/cm2) on two consecutive days post-culture was applied to two types of stem cells (hPDLSCs and SHED). The Quantitative Real-time Polymerase Chain Reaction (RT-qPCR) test was undertaken to investigate Vascular Endothelial Growth Factor-A (VEGF-A) and Angiopoietin I (ANG-I) genes on days 1, 3, 5, 7, and 10 after the first session of laser application. The 4′,6-diamidino-2-phenylindole (DAPI) staining and Methyl Thiazolyl Tetrazolium (MTT) test were conducted on days 1, 3, and 5 after the first session of laser application, to assess the cell viability. The Two-way ANOVA with Tukey post hoc test was used to analyze the outcomes of the MTT and RT-qPCR tests. The results of the MTT and DAPI convergently illustrated that the groups receiving photobiomodulation with 2.4 J/cm2 had higher cell viability compared to 3.9 J/cm2. All experimental groups showed an upregulation of VEGF-A and ANG-I gene expression from day 1 to 5, followed by a downregulation from day 5 to 10. The groups with cultured hPDLSCs and SHED receiving photobiomodulation using 2.4 J/cm2 had the most amounts of VEGF-A and ANG-I gene expression on day 5, respectively. In conclusion, the 660 nm mediated photobiomodulation therapy of cultured SHED and hPDLSCs with 2.4 J/cm2 energy density may be associated with higher angiogenic differentiation (the expression of VEGF-A and ANG-I) as well as higher cell viability compared to the photobiomodulation therapy with 3.9 J/cm2. [ABSTRACT FROM AUTHOR]

Background: Traditional Chinese medicine (TCM) has been hailed as a rich source of medicine, but many types of herbs and their functions still need to be rapidly discovered and elucidated. HerboChip, a target-based drug screening platform, is an array of different fractions deriving from herbal extracts. This study was designed to identify effective components from TCM that interact with vascular endothelial growth factor (VEGF) as a target using HerboChip. Methods: Selected TCMs that are traditionally used as remedies for cancer prevention and wound healing were determined and extracted with 50% ethanol. Biotinylated-VEGF was hybridized with over 500 chips coated with different HPLC-separated fractions from TCM extracts and straptavidin-Cy5 was applied to identify plant extracts containing VEGF-binding fractions. Cytotoxicity of selected herbal extracts and their activities on VEGF-mediated angiogenic functions were evaluated. Results: Over 500 chips were screened within a week, and ten positive hits were identified. The interaction of the identified herbal extracts with VEGF was confirmed in cultured endothelial cells. The identified herbs promoted or inhibited VEGF-mediated cell proliferation, migration and tube formation. Results from western blotting analysis demonstrated the identified herbal extracts significantly affected VEGF-triggered phosphorylations of eNOS, Akt and Erk. Five TCMs demonstrated potentiating activities on the VEGF response and five TCMs revealed suppressive activities. Conclusions: The current results demonstrated the applicability of the HerboChip platform and systematically elucidated the activity of selected TCMs on angiogenesis and its related signal transduction mechanisms. [ABSTRACT FROM AUTHOR]

This article reviews the latest research results of the use of ultrasound technology in the perioperative period of carotid endarterectomy and carotid stenting and discusses the role of ultrasound technology in accurately evaluating carotid stenosis and plaque stability, assisting in selecting the most suitable surgical method, and providing optimal perioperative imaging to guide carotid endarterectomy (CEA) and carotid artery stenting (CAS) to reduce the occurrence and progression of stroke.The research published in recent years on the application of ultrasound in the perioperative period of CEA and CAS was reviewed through the databases of CNKI, Pubmed, and Web of Science.Ultrasound has high clinical value in preoperative screening for indications, assessing the degree of carotid artery stenosis and the nature of plaque; monitoring hemodynamic changes intraoperatively to prevent cerebral ischemia or overperfusion; and evaluating surgical outcomes postoperatively and in late follow-up review.Ultrasound is currently widely used perioperatively in CEA and CAS and has even become the preferred choice of clinicians to evaluate the efficacy of surgery and follow-up. The presence of vulnerable plaque is an important risk factor for ischemic stroke. Contrast-enhanced ultrasound is an excellent tool to assess plaque stability. In most studies, ultrasound has been used only in a short follow-up period after CEA and CAS, and data from longer follow-ups are needed to provide more reliable evidence. [ABSTRACT FROM AUTHOR]

Background and purpose: Cardiovascular risk factors are known to contribute to the formation of atherosclerotic plaques, which can result in carotid stenosis. However, the extent to which these factors are associated with intraplaque neovascularization, a key indicator of plaque vulnerability, remains unclear. To investigate this relationship, a study was conducted utilizing contrast-enhanced ultrasound (CEUS) to assess intraplaque neovascularization in symptomatic patients. Methods: A cohort of 157 symptomatic patients underwent evaluation using Contrast-Enhanced Ultrasound (CEUS) imaging to assess carotid intraplaque neovascularization, which was quantified based on the degree of plaque enhancement. The collected data encompassed baseline patient characteristics, results from biochemical examinations, cardiovascular risk factors, and medication usage history. Regression analyses were conducted to elucidate the relationship between carotid plaque neovascularization and various cardiovascular risk factors. Results: Patients with intraplaque neovascularization were more prone to have diabetes mellitus (OR 3.81, 95% CI 1.94-7.46, p < 0.001), dyslipidemia (OR 2.36, 95% CI 1.22-4.55, p = 0.011) and hypertension (OR 2.92, 95% CI 1.50-5.71, p = 0.002). Smoking increased the risk of having intraplaque neovascularization (OR 2.25, 95% CI 1.12-4.54, p = 0.023). Treatment with statins was significantly lower in patients with intraplaque neovascularization (OR 0.37, 95% CI 0.19-0.72, p = 0.003). In the multivariate analysis, diabetes mellitus (OR 3.27, 95% CI 1.10-9.78, p = 0.034) was independently related to the presence of intraplaque neovascularization. Meanwhile, compared to the patients in the first tertile of serum glucose (< 6.20 mmol/L), the patients in the third tertile (> 13.35 mmol/L) had the most significance of intraplaque neovascularization (OR 5.55, 95% CI 1.85-16.66, p = 0.002). Conclusion: The findings indicated that diabetes mellitus is a significant cardiovascular risk factor that is strongly associated with carotid intraplaque neovascularization. [ABSTRACT FROM AUTHOR]

Introduction: Vascular Endothelial Growth Factor (VEGF) is associated with abnormal fundus neovascularization. Consequently, Anti-VEGF agents are vital for ophthalmic treatment. This paper reviews the application of anti-VEGF agents in ophthalmology over the past two decades with the aim of providing insights for further research. Methods: A meticulous search strategy was employed in the Web of Science Core Collection literature from 2003 to 2023 to gather relevant literature, which was then analyzed using VOSviewer, CiteSpace, and the R package Bibliometrix. Results: The study included 3,602 publications from 83 countries and 3,445 institutions. The United States and China have emerged as leading contributors in terms of the publication volume. Johns Hopkins University, the University of Sydney, and Genentech Inc were identified as frontrunners in this field. "Retina" had the highest publication volume, whereas "Ophthalmology" had the highest citation frequency. Among the 15,918 scholars, Bressler NM, Holz FG, Glassman AR, and Bandello F led in publication volume, while Brown DM was the most cited author. High-frequency keywords included "Endothelial Growth Factor," "Therapy," "Safety," and "Randomized Clinical Trial." Conclusion: Anti-VEGF drugs have shown notable success in treating neovascular eye diseases, especially wet age-related macular degeneration and diabetic macular edema, focusing on clinical efficacy, injection regimens, and safety. Future directions include developing new anti-VEGF drugs, drug delivery systems, non-invasive administration, multi-target drugs, leveraging big data and artificial intelligence, and addressing the current treatment limits. Continuous innovation and method improvement in this field promise more breakthroughs, providing effective, safe, and economical options for eye disease treatment. [ABSTRACT FROM AUTHOR]

Neovascular age-related macular degeneration (nAMD) remains a major cause of visual impairment and puts considerable burden on patients and health care systems. l-DOPA-treated Parkinson’s disease (PD) patients have been shown to be partially protected from nAMD, but the mechanism remains unknown. Using murine models that combine 1-methyl-4- phenyl-1,2,3,6-tetrahydropyridine-induced (MPTP-induced) PD and laser-induced nAMD with standard PD treatment of l-DOPA/DOPA-decarboxylase inhibitor or specific dopamine receptor inhibitors, we here demonstrate that l-DOPA treatment- induced increase of dopamine-mediated dopamine receptor D2 (DRD2) signaling inhibits choroidal neovascularization independently of MPTP-associated nigrostriatal pathway lesion. Analyzing a retrospective cohort of more than 200,000 patients with nAMD receiving anti-VEGF treatment from the French nationwide insurance database, we show that DRD2 agonist-treated PD patients have a significantly delayed age of onset of nAMD and reduced need for anti-VEGF therapies, similar to the effects of the l-DOPA treatment. While providing a mechanistic explanation for an intriguing epidemiological observation, our findings suggest that systemic DRD2 agonists might constitute an adjuvant therapy to delay and reduce the need for anti-VEGF therapy in patients with nAMD. [ABSTRACT FROM AUTHOR]

BACKGROUND: The precise association between lncRNA H19 and ferroptosis in the context of atherosclerosis remains uncertain. OBJECTIVE: This study is to clarify the underlying process and propose novel approaches for the advancement of therapeutic interventions targeting atherosclerosis. METHODS: Assessment of ferroptosis, which entails the evaluation of cell viability using CCK-8 and the quantification of intracellular MDA, GSH, and ferrous ions. Simultaneously, the protein expression levels of assessed by western blot analysis, while the expression level of lncRNA H19 was also determined. Furthermore, HAECs that were cultured with ox-LDL were subjected to Fer-1 interference. HAECs were exposed to ox-LDL and then transfected with H19 shRNA and H19 overexpression vector pcDNA3.1. The level of ferroptosis in the cells was then measured. Then, HAECs were subjected to incubation with ox-LDL, followed by transfection with H19 shRNA and treated with Erastin to assess the levels of ferroptosis, cell viability, and inflammatory factor production. and the ability for blood vessel development. RESULTS: The survival rate of HAECs in the ox-LDL group was much lower. Ox-LDL resulted in an upregulation of ACSL4 expression in HAECs, while the expression of SLC7A11 and GPX4 decreased. CONCLUSIONS: lncRNA H19 enhances ferroptosis and exacerbates arterial endothelial cell damage induced by LDL. [ABSTRACT FROM AUTHOR]

Drug resistance of malignant tumor leads to disease progression be the bottleneck in clinical treatment. Antiangiogenic therapy, which aims to "starve" the tumor by inhibiting angiogenesis, is one of the key strategies in clinical oncology treatments. Recently, dozens of investigational antibody drugs and biosimilars targeting angiogenesis have obtained regulatory approval for the treatment of various malignancies. Moreover, a new generation of bispecific antibodies based on the principle of antiangiogenesis are being advanced for clinical trial to overcome antiangiogenic resistance in tumor treatment or enhance the efficacy of monotherapy. Tumors often develop resistance to antiangiogenesis therapy, presenting as refractory and sometimes even resistant to new therapies, for which there are currently no effective management strategies. Thus, a detailed understanding of the mechanisms mediating resistance to antiangiogenesis antibodies is crucial for improving drug effectiveness and achieving a durable response to antiangiogenic therapy. In this review, we provide a novel perspective on the tumor microenvironment, including antibody structure, tumor stroma, and changes within tumor cells, to analyze the multifactorial reasons underlying resistance to antiangiogenesis antibodies. The review also enumerates biomarkers that indicate resistance and potential strategies for monitoring resistance. Furthermore, based on recent clinical and preclinical studies, we summarize potential strategies and translational clinical trials aimed at overcoming resistance to antiangiogenesis antibodies. This review provides a valuable reference for researchers and clinical practitioners involved in the development of new drugs or therapeutic strategies to overcome antiangiogenesis antibodies resistance. [ABSTRACT FROM AUTHOR]

Simple Summary: TGF-β is an important cytokine shown to drive oncogenesis in head and neck squamous cell carcinoma (HNSCC) through its diverse influences on the tumor microenvironment. While this cytokine is vital in maintaining tissue homeostasis in normal head and neck epithelia, in cancer, it paradoxically drives metastasis, angiogenesis, immune evasion, and therapy resistance. Despite promising preclinical data, the outcome of clinical trials of TGF-β inhibitors for HNSCC has been suboptimal. Patient stratification is warranted to improve this targeted therapy. Head and neck squamous cell carcinoma (HNSCC) is the sixth leading cause of cancer worldwide according to GLOBOCAN estimates from 2022. Current therapy options for recurrent or metastatic disease are limited to conventional cytotoxic chemotherapy and immunotherapy, with few targeted therapy options readily available. Recent single-cell transcriptomic analyses identified TGF-β signaling as an important mediator of functional interplays between cancer-associated fibroblasts and a subset of mesenchymal cancer cells. This signaling was shown to drive invasiveness, treatment resistance, and immune evasion. These data provide renewed interest in the TGF-β pathway as an alternative therapeutic target, prompting a critical review of previous clinical data which suggest a lack of benefit from TGF-β inhibitors. While preclinical data have demonstrated the great anti-tumorigenic potential of TGF-β inhibitors, the underwhelming results of ongoing and completed clinical trials highlight the difficulty actualizing these benefits into clinical practice. This topical review will discuss the relevant preclinical and clinical findings for TGF-β inhibitors in HNSCC and will explore the potential role of patient stratification in the development of this therapeutic strategy. [ABSTRACT FROM AUTHOR]

This article reviews innovative diagnostic approaches for diabetic retinopathy as the prevalence of diabetes mellitus and its complications continue to escalate. Novel techniques focus on early disease detection. Technological innovations, such as teleophthalmology, smartphone-based photography, artificial intelligence with deep learning, or widefield photography, can enhance diagnostic accuracy and accelerate the treatment. The review highlights teleophthalmology and handheld photography as promising solutions for remote eye care. These methods revolutionize diabetic retinopathy screening, offering cost-effective and accessible solutions. However, the use of these techniques may be limited by insurance coverage in certain world regions. Ultra-widefield photography offers a comprehensive view of up to 80.0% of the retina in a single image, compared to the 34.0% coverage of the traditional seven-field imaging protocol. It allows retinal imaging without pupil dilation, especially for individuals with compromised mydriasis. However, they also have drawbacks, including high costs, artifacts from eyelashes, eyelid margins, and peripheral distortion. Recent advances in artificial intelligence and machine learning, particularly through convolutional neural networks, are revolutionizing diabetic retinopathy diagnostics, enhancing screening efficiency and accuracy. FDA-approved Artificial Intelligence-powered devices such as LumineticsCore™, EyeArt, and AEYE Diagnostic Screening demonstrate high sensitivity and specificity in diabetic retinopathy detection. While Artificial Intelligence offers the potential to improve patient outcomes and reduce treatment costs, challenges such as dataset biases, high initial costs, and cybersecurity risks must be considered to ensure safety and efficiency. Nanotechnology advancements further enhance diagnosis, offering highly branched polyethyleneimine particles with fluorescein sodium (PEI-NHAc-FS) for better fluorescein angiography or vanadium oxide-based metabolic fingerprinting for early detection. [ABSTRACT FROM AUTHOR]

This study focused on investigating the mechanism of the astragaloside IV-induced bone marrow mesenchymal stem cell exosome (AS-IV-MSC-exo)/microRNA(miR)-411/HIF-1α axis in affecting vascular neovascularization and protecting cardiac function in myocardial infarction (MI) mice. Exosomes (MSC-exo and AS-IV-MSC-exo) were separated by differential centrifugation and then characterized. MI mouse models were established by left anterior descending coronary artery ligation. Echocardiography was used to evaluate cardiac function. HE staining and Masson staining were performed to observe myocardial histopathology. Capillary density in the myocardium via immunohistochemistry and quantified the expression of vascular endothelial growth factor (VEGF) via RT-qPCR. The expression of miR-411 and HIF-1α was tested by RT-qPCR and western blot and the targeting relationship of miR-411 and HIF-1α was verified by bioinformatics website and dual luciferase reporter gene assay. Exosomes with lipid bi-layer membrane structure, expressing exosomal surface marker proteins, and being taken up by cardiomyocytes could be successfully isolated utilizing ultracentrifugation. Intramyocardial injection of MSC-exo could restore cardiac function, decrease myocardial pathological changes and collagen deposition, and promote neovascularization in MI mice; the effect of AS-IV-MSC-exo was more significant. The ability of AS-IV-MSC-exo to restore cardiac function, lower myocardial pathological changes and collagen deposition, and promote neovascularization in MI mice was diminished when miR-411 expression in AS-IV-MSC-exo was reduced. Mechanistically, miR-411 was found to target and inhibit HIF-1α expression. Overexpression of HIF-1α impaired the impact of AS-IV-MSC-exo on improving cardiac function and promoting neovascularization in MI mice. AS-IV-MSC-exo improves cardiac function and promoted neovascularization via the miR-411/HIF-1α axis, thereby ameliorating MI. [ABSTRACT FROM AUTHOR]

Summary: Objective: Children with overweight/obesity (OW/OB) exhibit poor cardiometabolic health, yet mechanisms influencing brain health remain unclear. We examined the differences in neurological‐related circulating proteins in plasma among children with metabolically healthy obesity (MHO) and metabolically unhealthy obesity (MUO) and the association with metabolic syndrome markers. Methods: In this cross‐sectional study, we included 84 Caucasian children (39% girls), aged 10.1 ± 1.1 years, from the ActiveBrains project (NCT02295072). A ninety‐two‐protein targeted approach using Olink's® technology was used. Results: We identified distinct concentrations of CD38, LAIR2, MANF and NRP2 proteins in MHO compared with MUO. Moreover, individual metabolic syndrome (MS) markers were linked to nine proteins (CD38, CPM, EDA2R, IL12, JAMB, KYNU, LAYN, MSR1 and SMOC2) in children with OW/OB. These proteins play crucial roles in diverse biological processes (e.g., angiogenesis, cholesterol transport, nicotinamide adenine dinucleotide (NAD+) catalysis and maintenance of blood–brain barrier) related to brain health. Conclusion: Our proteomics study suggests that cardiometabolic health (represented by MHO/MUO or individual MS markers) is associated with the concentration in plasma of several proteins involved in brain health. Larger‐scale studies are needed to contrast/confirm these findings, with CD38 standing out as a particularly noteworthy and robust discovery. [ABSTRACT FROM AUTHOR]

Aim: Impaired wound healing in patients with diabetes can develop into nonhealing ulcerations. Because bone marrow mesenchymal stem cells (BMSCs) exosomes can promote wound healing, this study aims to investigate the mechanism of BMSCs‐isolated exosomal miR‐221‐3p in angiogenesis and diabetic wound healing. Methods: To mimic diabetes in vitro, human umbilical vein endothelial cells (HUVECs) were subjected to high glucose (HG). Exosomes were derived from BMSCs and identified by transmission electron microscopy (TEM), western blot analysis and dynamic light scattering (DLS). The ability to differentiate BMSCs was assessed via Oil red O staining, alkaline phosphatase (ALP) staining and alizarin red staining. The ability to internalise PKH26‐labelled exosomes was assessed using confocal microscopy. Migration, cell viability and angiogenesis were tested by scratch, MTT and tube formation assays separately. The miRNA and protein levels were analysed by quantitative reverse transcriptase polymerase chain reaction (qRT‐PCR) or western blotting. The relationship among miR‐221‐3p, FOXP1 and SPRY1 was determined using the dual‐luciferase reporter, ChIP and RIP assays. Results: Exosomal miR‐221‐3p was successfully isolated from BMSCs and delivered into HUVECs. HG was found to suppress the angiogenesis, cell viability and migration of HUVECs and exosomal miR‐221‐3p separated from BMSCs inhibited the above phenomenon. FOXP1 could transcriptionally upregulate SPRY1, and the silencing of FOXP1 reversed the HG‐stimulated angiogenesis inhibition, cell viability and migration in HUVECs via the downregulation of SPRY1. Meanwhile, miR‐221‐3p directly targeted FOXP1 and the overexpression of FOXP1 reversed the positive effect of exosomal miR‐221‐3p on HUVEC angiogenesis. Conclusion: Exosomal miR‐221‐3p isolated from BMSCs promoted angiogenesis in diabetic wounds through the mediation of the FOXP1/SPRY1 axis. Furthermore, the findings of this study can provide new insights into probing strategies against diabetes. [ABSTRACT FROM AUTHOR]

Purpose: To assess the manifestations of birdshot chorioretinitis (BSCR) in patients aged 80 and over. Design: Among patients with BSCR followed in the CO-BIRD prospective cohort (ClinicalTrials.gov Identifier: NCT05153057), we analyzed the subgroup of patients aged 80 and over. Methods: Patients were assessed in a standardized manner. Confluent atrophy was defined as hypoautofluorescent spots on fundus autofluorescence (FAF). Results: We included 39 (8.8%) of the 442 enrolled CO-BIRD patients. The mean age was 83.8 ± 3.7 years. The mean logMAR BCVA was 0.52 ± 0.76, with 30 patients (76.9%) having 20/40 or better in at least one eye. Thirty-five (89.7%) patients were receiving no treatment. Confluent atrophy in the posterior pole, disrupted retrofoveal ellipsoid zone and choroidal neovascularization were associated with logMAR BCVA >0.3 (p <.0001). Conclusion: In patients aged 80 and over we observed a striking heterogeneity of outcomes, but most retained a BCVA that allowed them to drive. [ABSTRACT FROM AUTHOR]

Objectives: To identify the effect of distribution characteristic of macrophages on placental function and angiogenesis in pregnancies with preeclampsia (PE) in presence of fetal growth restriction (FGR) or preeclampsia without FGR. Material and methods: The study tested the hypothesis that there was association between distribution characteristic of macrophage subsets (marked by CD68, CD163, respectively) and placental capillary development, leading to placental dysfunction in PE pregnancies with FGR (n = 36). Changes in placental parameters related with efficiency and angiogenesis and macrophage phenotypes (CD68 and CD163) were evaluated by immunohistochemistry. Pearson correlation analysis was performed to analysis the association between macrophage phenotype and placental function as well the CD34 staining, respectively. Additionally, the localization of CD68 and CD163 was assessed by using immunoflurorescence staining. Results: Pearson correlation analysis had shown the positive association between CD68 expression and microvessel formation and the reverse linear relationship between CD163 staining and placental sufficiency in PE + FGR placenta. The co-localization of CD163 and CD34 may pointed to the compensatory role of CD163 distribution involved in prompting neovascularization. Conclusions: The association between disturbed distribution of macrophages and placental efficiency and angiogenesis were only found in PE with FGR not in PE pregnancies without FGR, underlying the discrepancy role of macrophage subsets depending on the clinical phenotype of PE pregnancies. [ABSTRACT FROM AUTHOR]