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Cell Death & Disease Jul 2023Pulmonary fibrosis is a devastating disease, in which fibrotic tissue progressively replaces lung alveolar structure, resulting in chronic respiratory failure. Alveolar...
Pulmonary fibrosis is a devastating disease, in which fibrotic tissue progressively replaces lung alveolar structure, resulting in chronic respiratory failure. Alveolar type II cells act as epithelial stem cells, being able to transdifferentiate into alveolar type I cells, which mediate gas exchange, thus contributing to lung homeostasis and repair after damage. Impaired epithelial transdifferentiation is emerging as a major pathogenetic mechanism driving both onset and progression of fibrosis in the lung. Here, we show that lung endothelial cells secrete angiocrine factors that regulate alveolar cell differentiation. Specifically, we build on our previous data on the anti-fibrotic microRNA-200c and identify the Vascular Endothelial Growth Factor receptor 1, also named Flt1, as its main functional target in endothelial cells. Endothelial-specific knockout of Flt1 reproduces the anti-fibrotic effect of microRNA-200c against pulmonary fibrosis and results in the secretion of a pool of soluble factors and matrix components able to promote epithelial transdifferentiation in a paracrine manner. Collectively, these data indicate the existence of a complex endothelial-epithelial paracrine crosstalk in vitro and in vivo and position lung endothelial cells as a relevant therapeutic target in the fight against pulmonary fibrosis.
Topics: Humans; Pulmonary Fibrosis; Cell Transdifferentiation; Endothelial Cells; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-1; Lung; Alveolar Epithelial Cells; MicroRNAs
PubMed: 37454154
DOI: 10.1038/s41419-023-05962-2 -
Astrocytoma and glioblastoma IDH1-wildtype cells colonize tumor vessels and deploy vascular mimicry.Ultrastructural Pathology Jul 2023Gliomas are the most prevalent type of malignant brain tumors with a very dismal prognosis. Angiogenesis in glioma has recently gotten more attention and its molecular...
Gliomas are the most prevalent type of malignant brain tumors with a very dismal prognosis. Angiogenesis in glioma has recently gotten more attention and its molecular aspects have been published; however, these were not complemented with ultrastructural evidence. Our ultrastructural examination of glioma vessels reveals several unique and critical features related to their mechanisms of progression and metastasis strategy. The detailed ultrastructural survey of 18 isocitrate dehydrogenase-wildtype (IDH1-wt) glioblastomas and 12 isocitrate dehydrogenase-mutant (IDH1-mt) High-grade gliomas indicated that tumor vessels of both types had undergone deformities such as the thickening of the vessel wall (VW) and proliferation of the basement membrane, contour distortions, abnormal and discontinuous basal lamina, tumor cells' invasion and colonization of VW, disappearance of endothelial cells (ECs), pericytes, and smooth muscle cells, as well as the formation of a continuous ring of tumor cells attached to the luminal side of VW in numerous cases. The latter feature is a clear sign of vascular mimicry (VM) that was previously suggested in gliomas but never shown by TEM. Additionally, the vascular invasion was carried out by a large number of tumor cells and was accompanied by the accumulation of tumor lipids in the vessels' lumina and VWs; these two features are distinct for gliomas and may alter the course of the clinical presentation and overall prognosis. This raises the issue of how to specifically target tumor cells involved in vascular invasion in order to optimize prognosis and overcome these mechanisms employed by the tumor cells.
Topics: Humans; Glioblastoma; Isocitrate Dehydrogenase; Endothelial Cells; Astrocytoma; Glioma; Brain Neoplasms; Mutation
PubMed: 37144386
DOI: 10.1080/01913123.2023.2205927 -
Biochimica Et Biophysica Acta.... Apr 2024Exchange protein directly activated by cAMP 1 (EPAC1), a major isoform of guanine nucleotide exchange factors, is highly expressed in vascular endothelia cells and...
AIMS
Exchange protein directly activated by cAMP 1 (EPAC1), a major isoform of guanine nucleotide exchange factors, is highly expressed in vascular endothelia cells and regulates angiogenesis in the retina. High intratumor microvascular densities (MVD) resulting from angiogenesis is responsible for breast cancer development. Downregulation of EPAC1 in tumor cell reduces triple-negative breast cancer (TNBC)-induced angiogenesis. However, whether Epac1 expressed in vascular endothelial cells contributes to angiogenesis and tumor development of TNBC remains elusive.
MAIN METHODS
We employed NY0123, a previously identified potent EPAC inhibitor, to explore the anti-angiogenic biological role of EPAC1 in vitro and in vivo through vascular endothelial cells, rat aortic ring, Matrigel plug, and chick embryo chorioallantoic membrane (CAM) and yolk sac membrane (YSM) assays, as well as the in vivo xenograft tumor models of TNBC in both chick embryo and mice.
KEY FINDINGS
Inhibiting EPAC1 in vascular endothelial cells by NY0123 significantly suppresses angiogenesis and tumor growth of TNBC. In addition, NY0123 possesses a better inhibitory efficacy than ESI-09, a reported specific EPAC inhibitor tool compound. Importantly, inhibiting EPAC1 in vascular endothelia cells regulates the typical angiogenic signaling network, which is associated with not only vascular endothelial growth factor (VEGF)/vascular endothelial growth factor receptor-2 (VEGFR2) signaling, but also PI3K/AKT, MEK/ERK and Notch pathway.
CONCLUSIONS
Our findings support that EPAC1 may serve as an effective anti-angiogenic therapeutic target of TNBC, and EPAC inhibitor NY0123 has the therapeutic potential to be developed for the treatment of TNBC.
Topics: Animals; Chick Embryo; Humans; Mice; Rats; Endothelial Cells; Guanine Nucleotide Exchange Factors; Phosphatidylinositol 3-Kinases; Triple Negative Breast Neoplasms; Vascular Endothelial Growth Factor A; Neovascularization, Pathologic
PubMed: 38447883
DOI: 10.1016/j.bbadis.2024.167114 -
Biomolecules Dec 2023Vascular calcification (VC) is an age-related complication characterised by calcium-phosphate deposition in the arterial wall driven by the osteogenic transformation of...
Vascular calcification (VC) is an age-related complication characterised by calcium-phosphate deposition in the arterial wall driven by the osteogenic transformation of vascular smooth muscle cells (VSMCs). The JAK-STAT pathway is an emerging target in inflammation. Considering the relationship between VC and inflammation, we investigated the role of JAK-STAT signalling during VSMC calcification. Human aortic smooth muscle cells (HASMCs) were cultured in high-inorganic phosphate (Pi) medium for up to 7 days; calcium deposition was determined via Alizarin staining and colorimetric assay. Inflammatory factor secretion was evaluated via ELISA and JAK-STAT members' activation using Western blot or immunohistochemistry on HASMCs or calcified aortas of Vitamin D-treated C57BL6/J mice, respectively. The JAK-STAT pathway was blocked by JAK Inhibitor I and Von Kossa staining was used for calcium deposits in murine aortic rings. During Pi-induced calcification, HASMCs released IL-6, IL-8, and MCP-1 and activated JAK1-JAK3 proteins and STAT1. Phospho-STAT1 was detected in murine calcified aortas. Blocking of the JAK-STAT cascade reduced HASMC proliferation and pro-inflammatory factor expression and release while increasing calcium deposition and osteogenic transcription factor RUNX2 expression. Consistently, JAK-STAT pathway inhibition exacerbates mouse aortic ring calcification ex vivo. Intriguingly, our results suggest an alternative link between VSMC inflammation and VC.
Topics: Humans; Animals; Mice; Muscle, Smooth, Vascular; Calcium; Janus Kinases; STAT Transcription Factors; Signal Transduction; Vascular Calcification; Inflammation
PubMed: 38254629
DOI: 10.3390/biom14010029 -
Journal of Thoracic Imaging Jul 2023Arterial plaque rupture and thrombosis is the primary cause of major cardiovascular and neurovascular events. The identification of atherosclerosis, especially high-risk... (Review)
Review
Arterial plaque rupture and thrombosis is the primary cause of major cardiovascular and neurovascular events. The identification of atherosclerosis, especially high-risk plaques, is therefore crucial to identify high-risk patients and to implement preventive therapies. Computed tomography angiography has the ability to visualize and characterize vascular plaques. The standard methods for plaque evaluation rely on the assessment of plaque burden, stenosis severity, the presence of positive remodeling, napkin ring sign, and spotty calcification, as well as Hounsfield Unit (HU)-based thresholding for plaque quantification; the latter with multiple shortcomings. Semiautomated threshold-based segmentation techniques with predefined HU ranges identify and quantify limited plaque characteristics, such as low attenuation, non-calcified, and calcified plaque components. Contrary to HU-based thresholds, histologically validated plaque characterization, and quantification, an emerging Artificial intelligence-based approach has the ability to differentiate specific tissue types based on a biological correlate, such as lipid-rich necrotic core and intraplaque hemorrhage that determine plaque vulnerability. In this article, we review the relevance of plaque characterization and quantification and discuss the benefits and limitations of the currently available plaque assessment and classification techniques.
Topics: Humans; Coronary Artery Disease; Artificial Intelligence; Coronary Angiography; Plaque, Atherosclerotic; Tomography, X-Ray Computed; Computed Tomography Angiography; Coronary Vessels; Predictive Value of Tests
PubMed: 37115957
DOI: 10.1097/RTI.0000000000000711 -
Cellular and Molecular Life Sciences :... Aug 2023Exposure to chronic psychological stress (CPS) is an intractable risk factor for inflammatory and metabolic diseases. Lysosomal cysteinyl cathepsins play an important...
Exposure to chronic psychological stress (CPS) is an intractable risk factor for inflammatory and metabolic diseases. Lysosomal cysteinyl cathepsins play an important role in human pathobiology. Given that cathepsin S (CTSS) is upregulated in the stressed vascular and adipose tissues, we investigated whether CTSS participates in chronic stress-induced skeletal muscle mass loss and dysfunction, with a special focus on muscle protein metabolic imbalance and apoptosis. Eight-week-old male wildtype (CTSS) and CTSS-knockout (CTSS) mice were randomly assigned to non-stress and variable-stress groups. CTSS stressed mice showed significant losses of muscle mass, dysfunction, and fiber area, plus significant mitochondrial damage. In this setting, stressed muscle in CTSS mice presented harmful alterations in the levels of insulin receptor substrate 2 protein content (IRS-2), phospho-phosphatidylinositol 3-kinase, phospho-protein kinase B, and phospho-mammalian target of rapamycin, forkhead box-1, muscle RING-finger protein-1 protein, mitochondrial biogenesis-related peroxisome proliferator-activated receptor-γ coactivator-α, and apoptosis-related B-cell lymphoma 2 and cleaved caspase-3; these alterations were prevented by CTSS deletion. Pharmacological CTSS inhibition mimics its genetic deficiency-mediated muscle benefits. In CC cells, CTSS silencing prevented stressed serum- and oxidative stress-induced IRS-2 protein reduction, loss of the myotube myosin heavy chain content, and apoptosis accompanied by a rectification of investigated molecular harmful changes; these changes were accelerated by CTSS overexpression. These findings demonstrated that CTSS plays a role in IRS-2-related protein anabolism and catabolism and cell apoptosis in stress-induced muscle wasting, suggesting a novel therapeutic strategy for the control of chronic stress-related muscle disease in mice under our experimental conditions by regulating CTSS activity.
Topics: Animals; Male; Mice; Adipose Tissue; Cathepsins; Muscles; Muscular Atrophy; Stress, Physiological
PubMed: 37589754
DOI: 10.1007/s00018-023-04888-4 -
Stroke and Vascular Neurology Dec 2023The ring finger protein 213 gene () p.R4810K variant increased the risk of acute ischaemic stroke (AIS) attributable to intracranial arterial stenosis (ICAS) in the...
BACKGROUND AND PURPOSE
The ring finger protein 213 gene () p.R4810K variant increased the risk of acute ischaemic stroke (AIS) attributable to intracranial arterial stenosis (ICAS) in the Japanese and Korean populations. In this study, we aimed to examine the prevalence of the p.R4810K variant in Chinese patients with AIS or transient ischaemic attack and identify the phenotype of the carriers.
METHODS
We analysed data from the Third China National Stroke Registry. All included participants were divided into two groups by carrier status of the p.R4810K variant. The aetiological classification was conducted according to the Trial of Org 10172 in Acute Stroke Treatment (TOAST) criteria. The presence of ICAS and extracranial arterial stenosis (ECAS) was defined as 50%-99% stenosis or occlusion of any intracranial and extracranial artery. Logistic regression models and Cox regression models were used to evaluate the association of the p.R4810K variant with TOAST classification, stenosis phenotypes and clinical outcomes.
RESULTS
A total of 10 381 patients were enrolled, among which 56 (0.5%) had the heterozygote GA genotype for p.R4810K. The variant carriers were younger (p=0.01), and more likely to suffer from peripheral vascular disease (p=0.04). The p.R4810K variant was associated with large-artery atherosclerosis (LAA) (adjusted OR=1.94, 95% CI 1.13 to 3.33), anterior circulation stenosis (adjusted OR=2.12, 95% CI 1.23 to 3.65) and ECAS (adjusted OR=2.29, 95% CI 1.16 to 4.51). Nevertheless, the p.R4810K variant was not associated with recurrence, poor functional outcome and mortality at 3 months and 1 year.
CONCLUSIONS
The p.R4810K variant was associated with LAA, anterior circulation stenosis and ECAS in Chinese patients. Given the low carrying rate and only 1-year follow-up information, caution should be taken to interpret our findings in no statistically significant association between the p.R4810K variant and stroke prognosis in Chinese patients.
Topics: Humans; Ischemic Attack, Transient; Constriction, Pathologic; Stroke; Brain Ischemia; Genetic Predisposition to Disease; Phenotype; Ischemic Stroke; Atherosclerosis; Adenosine Triphosphatases; Ubiquitin-Protein Ligases
PubMed: 37137523
DOI: 10.1136/svn-2022-002276 -
Nature Communications Apr 2024Heart failure with preserved ejection fraction (HFpEF) is associated with endothelial dysfunction. We have previously reported that statins prevent endothelial...
Heart failure with preserved ejection fraction (HFpEF) is associated with endothelial dysfunction. We have previously reported that statins prevent endothelial dysfunction through inhibition of microRNA-133a (miR-133a). This study is to investigate the effects and the underlying mechanisms of statins on HFpEF. Here, we show that statins upregulate the expression of a circular RNA (circRNA-RBCK1) which is co-transcripted with the ring-B-box-coiled-coil protein interacting with protein kinase C-1 (RBCK1) gene. Simultaneously, statins increase activator protein 2 alpha (AP-2α) transcriptional activity and the interaction between circRNA-RBCK1 and miR-133a. Furthermore, AP-2α directly interacts with RBCK1 gene promoter in endothelial cells. In vivo, lovastatin improves diastolic function in male mice under HFpEF, which is abolished by loss function of endothelial AP-2α or circRNA-RBCK1. This study suggests that statins upregulate the AP-2α/circRNA-RBCK1 signaling to suppress miR-133a in cardiac endothelial cells and prevent diastolic dysfunction in HFpEF.
Topics: Animals; Male; Mice; Endothelial Cells; Heart Failure; Hydroxymethylglutaryl-CoA Reductase Inhibitors; MicroRNAs; RNA, Circular; Stroke Volume
PubMed: 38580662
DOI: 10.1038/s41467-024-47327-z -
BMC Cancer Jul 2023Clinical studies have shown that first-line use of anti-angiogenetic therapy can prolong progression-free survival but little progress has been made in extending the...
BACKGROUND
Clinical studies have shown that first-line use of anti-angiogenetic therapy can prolong progression-free survival but little progress has been made in extending the overall survival of the patients. We explored the role of ELK3 in glioma angiogenesis to improve and design more efficacious therapies.
METHODS
A tissue microarray and immunohistochemistry analysis were used to determine the expression of ELK3 protein in 400 glioma patients. Cell proliferation, metastasis, cell cycle, and apoptosis were monitored in U87 and U251 cells using CCK-8, EdU, transwell assays, and flow cytometry. A tube-formation assay, a rat aorta ring sprouting assay, and a matrigel plug assay were performed to examine the antiangiogenic activity of ELK3. An ELISA, Western blot, and correlation analysis of the CGGA dataset were used to detect the association between ELK3 and VEGF-A or ELK3 and HIF-1[Formula: see text]. Besides, orthotopic transplantation in nude mice and histopathological and immunological analysis of in vitro tumors were used to explore the effect of ELK3 on tumor progression and median survival.
RESULTS
ELK3 was upregulated in glioma tissues and associated with a poor prognosis. In vitro, ELK3 promoted cell proliferation and cell cycle progression, induced metastasis, and suppressed apoptosis. Then, silencing ELK3 inhibited VEGF-A expression and secretion by facilitating HIF-1[Formula: see text] degradation via ubiquitination. Finally, knockdown ELK3 inhibited tumor progression and angiogenesis in vitro and in vivo, as well as prolonged nude mice's median survival.
CONCLUSIONS
Our findings first evidenced that ELK3 is crucial for glioma because it promotes angiogenesis by activating the HIF-1[Formula: see text]/VEGF-A signaling axis. Therefore, we suggest that ELK3 is a prognostic marker with a great potential for glioma angiogenesis and ELK3-targeted therapeutic strategies might hold promise in improving the efficacy of anti-angiogenic therapies.
Topics: Animals; Mice; Mice, Nude; Vascular Endothelial Growth Factor A; Glioma; Signal Transduction; Cell Proliferation; Hypoxia-Inducible Factor 1; Cell Line, Tumor; Neovascularization, Pathologic
PubMed: 37452291
DOI: 10.1186/s12885-023-11069-w -
Association Between Airway Stenosis Degree and Respiratory Distress in Infants With a Vascular Ring.Cureus Oct 2023Background Although the number of cases of prenatally diagnosed vascular rings is increasing, some cases may remain asymptomatic, and no indicator of the appearance of...
Background Although the number of cases of prenatally diagnosed vascular rings is increasing, some cases may remain asymptomatic, and no indicator of the appearance of dyspnea has been established. Thus, we aimed to determine the relationship between the degree of airway compression by the vascular ring on contrast-enhanced computed tomography (CT) and respiratory distress. Methods This is a retrospective study of nine patients diagnosed with vascular rings at a single hospital from July 2010 to December 2019. Data regarding the patient's clinical characteristics, such as prenatal diagnosis, vascular ring type, complicated cardiac disease, and presence or absence of surgery, were recorded. Airway assessment on contrast-enhanced CT was measured in the axial cross-section. Statistical analysis was performed using Statistical Product and Service Solutions (SPSS) (version 25.0; IBM SPSS Statistics for Windows, Armonk, NY). Results Five of the eight patients had respiratory distress. Patients with respiratory distress were less likely to have been diagnosed prenatally (p = 0.04) and had smaller stenosis degree of anteroposterior diameter (p = 0.03). Conclusion Contrast-enhanced CT is useful in patients with vascular rings. Our study suggests that the stenosis degree of the anterior-posterior diameter of the airway is related to dyspnea.
PubMed: 37965390
DOI: 10.7759/cureus.47022