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The Journal of Cell Biology Sep 2023Polydom is an extracellular matrix protein involved in lymphatic vessel development. Polydom-deficient mice die immediately after birth due to defects in lymphatic...
Polydom is an extracellular matrix protein involved in lymphatic vessel development. Polydom-deficient mice die immediately after birth due to defects in lymphatic vessel remodeling, but the mechanism involved is poorly understood. Here, we report that Polydom directly binds to Tie1, an orphan receptor in the Angiopoietin-Tie axis, and facilitates migration of lymphatic endothelial cells (LECs) in a Tie1-dependent manner. Polydom-induced LEC migration is diminished by PI3K inhibitors but not by an ERK inhibitor, suggesting that the PI3K/Akt signaling pathway is involved in Polydom-induced LEC migration. In line with this possibility, Akt phosphorylation in LECs is enhanced by Polydom although no significant Tie1 phosphorylation is induced by Polydom. LECs also exhibited nuclear exclusion of Foxo1, a signaling event downstream of Akt activation, which was impaired in Polydom-deficient mice. These findings indicate that Polydom is a physiological ligand for Tie1 and participates in lymphatic vessel development through activation of the PI3K/Akt pathway.
Topics: Animals; Mice; Endothelial Cells; Lymphatic Vessels; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Receptor, TIE-1; Calcium-Binding Proteins; Cell Movement
PubMed: 37338522
DOI: 10.1083/jcb.202208047 -
Trends in Endocrinology and Metabolism:... Jun 2024The regulation of triglyceride (TG) tissue distribution, storage, and utilization, a fundamental process of energy homeostasis, critically depends on lipoprotein lipase... (Review)
Review
The regulation of triglyceride (TG) tissue distribution, storage, and utilization, a fundamental process of energy homeostasis, critically depends on lipoprotein lipase (LPL). We review the intricate mechanisms by which LPL activity is regulated by angiopoietin-like proteins (ANGPTL3, 4, 8), apolipoproteins (APOA5, APOC3, APOC2), and the cAMP-responsive element-binding protein H (CREBH). ANGPTL8 functions as a molecular switch, through complex formation, activating ANGPTL3 while deactivating ANGPTL4 in their LPL inhibition. The ANGPTL3-4-8 model integrates the roles of the aforementioned proteins in TG partitioning between white adipose tissue (WAT) and oxidative tissues (heart and skeletal muscles) during the feed/fast cycle. This model offers a unified perspective on LPL regulation, providing insights into TG metabolism, metabolic diseases, and therapeutics.
Topics: Humans; Lipoprotein Lipase; Animals; Triglycerides; Angiopoietin-like Proteins; Angiopoietin-Like Protein 8; Angiopoietin-Like Protein 4; Angiopoietin-Like Protein 3
PubMed: 38521668
DOI: 10.1016/j.tem.2024.02.016 -
Scientific Reports Aug 2023Endothelial cells cover the lining of different blood vessels and lymph nodes, and have major functions including the transport of blood, vessel homeostasis,...
Endothelial cells cover the lining of different blood vessels and lymph nodes, and have major functions including the transport of blood, vessel homeostasis, inflammatory responses, control of transendothelial migration of circulating cells into the tissues, and formation of new blood vessels. Therefore, understanding these cells is of major interest. The morphological features, phenotype and function of endothelial cells varies according to the vascular bed examined. The sialomucin, CD34, is widely used as an endothelial marker. However, CD34 is differentially expressed on endothelial cells in different organs and in pathological conditions. Little is known about regulation of endothelial CD34 expression or function. Expression of CD34 is also strongly regulated in-vitro in endothelial cell models, including human umbilical vein endothelial cells (HUVEC) and endothelial colony forming cells (ECFC). We have therefore analysed the expression and function of CD34 by comparing CD34 and CD34 endothelial cell subpopulations. Transcriptomic analysis showed that CD34 gene and protein expressions are highly correlated, that CD34 cells proliferate less but express higher levels of IL-33 and Angiopoietin 2, compared with CD34 cells. Higher secretion levels of IL-33 and Angiopoietin 2 by CD34 HUVECs was confirmed by ELISA. Finally, when endothelial cells were allowed to interact with peripheral blood mononuclear cells, CD34 endothelial cells activated stronger proliferation of regulatory T lymphocytes (Tregs) compared to CD34 cells whereas expansion of other CD4-T cell subsets was equivalent. These results suggest that CD34 expression by endothelial cells in-vitro associates with their ability to proliferate and with an immunogenic ability that favours the tolerogenic response.
Topics: Humans; Angiopoietin-2; Interleukin-33; Leukocytes, Mononuclear; Antigens, CD34; Cell Adhesion Molecules; Human Umbilical Vein Endothelial Cells
PubMed: 37598252
DOI: 10.1038/s41598-023-40622-7 -
The Journal of Clinical Investigation Oct 2023Improving the management of metastasis in pancreatic neuroendocrine tumors (PanNETs) is critical, as nearly half of patients with PanNETs present with liver metastases,...
Improving the management of metastasis in pancreatic neuroendocrine tumors (PanNETs) is critical, as nearly half of patients with PanNETs present with liver metastases, and this accounts for the majority of patient mortality. We identified angiopoietin-2 (ANGPT2) as one of the most upregulated angiogenic factors in RNA-Seq data from human PanNET liver metastases and found that higher ANGPT2 expression correlated with poor survival rates. Immunohistochemical staining revealed that ANGPT2 was localized to the endothelial cells of blood vessels in PanNET liver metastases. We observed an association between the upregulation of endothelial ANGPT2 and liver metastatic progression in both patients and transgenic mouse models of PanNETs. In human and mouse PanNET liver metastases, ANGPT2 upregulation coincided with poor T cell infiltration, indicative of an immunosuppressive tumor microenvironment. Notably, both pharmacologic inhibition and genetic deletion of ANGPT2 in PanNET mouse models slowed the growth of PanNET liver metastases. Furthermore, pharmacologic inhibition of ANGPT2 promoted T cell infiltration and activation in liver metastases, improving the survival of mice with metastatic PanNETs. These changes were accompanied by reduced plasma leakage and improved vascular integrity in metastases. Together, these findings suggest that ANGPT2 blockade may be an effective strategy for promoting T cell infiltration and immunostimulatory reprogramming to reduce the growth of liver metastases in PanNETs.
Topics: Animals; Humans; Mice; Angiopoietin-2; Endothelial Cells; Liver Neoplasms; Mice, Transgenic; Neuroendocrine Tumors; Pancreatic Neoplasms; T-Lymphocytes; Tumor Microenvironment
PubMed: 37843277
DOI: 10.1172/JCI167994 -
Communications Biology Sep 2023Use of immune checkpoint inhibitors (ICIs) as cancer immunotherapy advances rapidly in the clinic. Despite their therapeutic benefits, ICIs can cause clinically...
Use of immune checkpoint inhibitors (ICIs) as cancer immunotherapy advances rapidly in the clinic. Despite their therapeutic benefits, ICIs can cause clinically significant immune-related adverse events (irAEs), including myocarditis. However, the cellular and molecular mechanisms regulating irAE remain unclear. Here, we investigate the function of Angiopoietin-like protein 2 (ANGPTL2), a potential inflammatory mediator, in a mouse model of ICI-related autoimmune myocarditis. ANGPTL2 deficiency attenuates autoimmune inflammation in these mice, an outcome associated with decreased numbers of T cells and macrophages. We also show that cardiac fibroblasts express abundant ANGPTL2. Importantly, cardiac myofibroblast-derived ANGPTL2 enhances expression of chemoattractants via the NF-κB pathway, accelerating T cell recruitment into heart tissues. Our findings suggest an immunostimulatory function for ANGPTL2 in the context of ICI-related autoimmune inflammation and highlight the pathophysiological significance of ANGPTL2-mediated cardiac myofibroblast/immune cell crosstalk in enhancing autoimmune responses. These findings overall provide insight into mechanisms regulating irAEs.
Topics: Animals; Mice; Angiopoietin-Like Protein 2; Heart; Immune Checkpoint Inhibitors; Inflammation; Myocarditis
PubMed: 37736764
DOI: 10.1038/s42003-023-05338-4 -
Frontiers in Pediatrics 2023Kaposiform lymphangiomatosis (KLA) is a rare and complex lymphatic anomaly with a poor prognosis. There is no standard treatment, and drug therapies are the most common...
INTRODUCTION
Kaposiform lymphangiomatosis (KLA) is a rare and complex lymphatic anomaly with a poor prognosis. There is no standard treatment, and drug therapies are the most common therapeutic method. However, some patients' symptoms become gradually aggravated despite medical treatment. Splenectomy may be an alternative option when pharmacological therapies are ineffective.
MATERIALS AND METHODS
We reviewed and evaluated the cases of 3 patients with KLA who ultimately underwent splenectomy. Results: The lesions were diffusely distributed and involved the lungs and spleens of the 3 patients. Laboratory examinations revealed that all three patients had thrombocytopenia and reduced fibrinogen levels. All patients underwent symptomatic splenectomy after the medication failed. Surprisingly, their symptoms greatly improved. Histopathological investigation of the splenic lesions of the three patients confirmed the diagnosis of KLA. Immunohistochemical staining showed positivity for CD31, CD34, podoplanin, Prox-1 and angiopoietin 2 (Ang-2).
DISCUSSION
This study aimed to review the features of KLA patients treated by splenectomy and explore the underlying link between splenectomy and prognosis. The reason for the improvement after splenectomy may be related to increased Ang-2 levels and platelet activation in patients with KLA. Future research should seek to develop more targeted drugs based on molecular findings, which may give new hope for the treatment of KLA.
PubMed: 37664553
DOI: 10.3389/fped.2023.1203336 -
Cell Communication and Signaling : CCS Feb 2024Diabetic kidney disease (DKD) is a long-term and serious complication of diabetes that affects millions of people worldwide. It is characterized by proteinuria,... (Review)
Review
Diabetic kidney disease (DKD) is a long-term and serious complication of diabetes that affects millions of people worldwide. It is characterized by proteinuria, glomerular damage, and renal fibrosis, leading to end-stage renal disease, and the pathogenesis is complex and involves multiple cellular and molecular mechanisms. Among three kinds of intraglomerular cells including podocytes, glomerular endothelial cells (GECs) and mesangial cells (MCs), the alterations in one cell type can produce changes in the others. The cell-to-cell crosstalk plays a crucial role in maintaining the glomerular filtration barrier (GFB) and homeostasis. In this review, we summarized the recent advances in understanding the pathological changes and interactions of these three types of cells in DKD and then focused on the signaling pathways and factors that mediate the crosstalk, such as angiopoietins, vascular endothelial growth factors, transforming growth factor-β, Krüppel-like factors, retinoic acid receptor response protein 1 and exosomes, etc. Furthermore, we also simply introduce the application of the latest technologies in studying cell interactions within glomerular cells and new promising mediators for cell crosstalk in DKD. In conclusion, this review provides a comprehensive and updated overview of the glomerular crosstalk in DKD and highlights its importance for the development of novel intervention approaches.
Topics: Humans; Podocytes; Diabetic Nephropathies; Mesangial Cells; Endothelial Cells; Kidney Glomerulus; Diabetes Mellitus
PubMed: 38374141
DOI: 10.1186/s12964-024-01502-3 -
Ophthalmology and Therapy Oct 2023This review aims to assess the efficacy, durability and safety of faricimab-a dual vascular endothelial growth factor and angiopoietin 2 inhibitor-in patients with... (Review)
Review
INTRODUCTION
This review aims to assess the efficacy, durability and safety of faricimab-a dual vascular endothelial growth factor and angiopoietin 2 inhibitor-in patients with neovascular age-related macular degeneration (nAMD) and diabetic macula oedema (DMO). It summarises the findings of current studies on faricimab and discusses whether this new drug may fill a gap in current treatment options.
METHODS
We performed a search of the PubMed, Cochrane, Web of Science and EMBASE databases for publications on faricimab between 29 November 2022 and 10 May 2023, and a search of ClinicalTrials.gov for the protocols on clinical trials for this review. We included clinical trials, case-control studies and observational studies.
RESULTS
In phase 3 trials of nAMD, the efficacy of faricimab was non-inferior to aflibercept (+ 5.8-6.6 vs. + 5.1-6.6 Early Treatment Diabetic Retinopathy Study [ETDRS] letters). At study end, 80% of faricimab-treated patients were on ≥ 12-week dosing intervals, and 44.9-45.7% of faricimab-treated patients were on 16-week dosing intervals. Total adverse events, as well as serious ocular adverse events, were comparable between groups. In phase 3 trials of DMO, efficacy of faricimab was non-inferior to aflibercept (+ 10.7-11.8 vs. + 10.3-10.9 ETDRS letters). At study end, > 70% of patients in the personalised treatment interval faricimab group were on ≥ 12-week dosing intervals, and 51-53% were on 16-week dosing intervals. Total adverse events were comparable between groups, although the rate of serious ocular adverse events was higher in the faricimab groups than in the aflibercept groups (1.9-3.1% vs. 0.6-1.9%, respectively). In real-world studies of treatment-resistant nAMD or DMO, faricimab demonstrated superior efficacy compared to aflibercept. In a real-world study of mostly previously treated nAMD, faricimab demonstrated some efficacy.
CONCLUSION
Faricimab demonstrated non-inferior to superior efficacy, strong durability and acceptable safety in treatment-naïve nAMD and mostly treatment-naïve DMO, as well as superior efficacy in treatment-resistant nAMD and DMO. However, further research is needed on faricimab in real-world settings.
PubMed: 37410309
DOI: 10.1007/s40123-023-00753-6 -
Journal of Veterinary Internal Medicine 2023Hypothyroidism in dogs is associated with obesity and altered lipid and carbohydrate metabolism. The adipokines, visfatin, and betatrophin, affect glucose tolerance....
BACKGROUND
Hypothyroidism in dogs is associated with obesity and altered lipid and carbohydrate metabolism. The adipokines, visfatin, and betatrophin, affect glucose tolerance. Betatrophin is involved in lipid regulation.
HYPOTHESIS
Visfatin and betatrophin serum concentrations are altered in hypothyroid dogs.
ANIMALS
Dogs with naturally occurring hypothyroidism (n = 25) and healthy dogs (n = 25).
METHODS
Insulin, visfatin, and betatrophin serum concentrations were measured in all dogs and 19 of the hypothyroid dogs after 30 days of thyroxine treatment. Body condition score (BCS) was determined (1-9 scale).
RESULTS
Visfatin concentrations were lower in hypothyroid compared with healthy dogs (mean, 95% confidence interval [CI]; 2.0 ng/mL, 1.2-3.3 vs 5.1 ng/mL, 3.3-7.8; P = .004) and increased post-treatment (3.1 ng/mL, 1.9-4.9 vs 2.6 ng/mL, 1.6-4.1; P = .05). Betatrophin concentrations were lower in lean to normal (body condition score [BCS], 3-5) hypothyroid dogs compared to lean to normal healthy dogs (52 pg/mL, 9-307 vs 597 pg/mL, 216-1648; P = .03), but were not different between overweight (BCS, 6-9) hypothyroid and healthy dogs (341 pg/L, 168-695 vs 178 pg/mL, 77-415; P = .26), and decreased post-treatment in overweight dogs (206 pg/mL, 87-488 vs 268 pg/mL, 112-640; P = .004). Visfatin concentrations were higher in overweight compared with lean to normal dogs (4.7 ng/mL, 3.3-6.6 vs 2.2 ng/mL, 1.2-4.2; P = .04). Betatrophin concentrations were positively correlated with BCS (r = .47, P = .02) and insulin concentrations (r = .48, P = .03) in hypothyroid dogs and negatively correlated with BCS (r = -.47, P = .02) and thyroid stimulating hormone concentrations (r = -.56, P = .01) in healthy dogs.
CONCLUSIONS AND CLINICAL IMPORTANCE
Hypothyroidism in dogs is associated with alterations in visfatin and betatrophin concentrations that partially resolve with thyroxine treatment.
Topics: Dogs; Animals; Nicotinamide Phosphoribosyltransferase; Angiopoietin-Like Protein 8; Overweight; Thyroxine; Hypothyroidism; Insulin; Lipids; Dog Diseases
PubMed: 37864301
DOI: 10.1111/jvim.16904 -
Platelets Dec 2023Arterial tonometry and vascular calcification measures are useful in cardiovascular disease (CVD) risk assessment. Prior studies found associations between tonometry...
Arterial tonometry and vascular calcification measures are useful in cardiovascular disease (CVD) risk assessment. Prior studies found associations between tonometry measures, arterial calcium, and CVD risk. Activated platelets release angiopoietin-1 and other factors, which may connect vascular structure and platelet function. We analyzed arterial tonometry, platelet function, aortic, thoracic and coronary calcium, and thoracic and abdominal aorta diameters measured in the Framingham Heart Study Gen3/NOS/OMNI-2 cohorts ( = 3,429, 53.7% women, mean age 54.4 years ±9.3). Platelet reactivity in whole blood or platelet-rich plasma was assessed using 5 assays and 7 agonists. We analyzed linear mixed effects models with platelet reactivity phenotypes as outcomes, adjusting for CVD risk factors and family structure. Higher arterial calcium trended with higher platelet reactivity, whereas larger aortic diameters trended with lower platelet reactivity. Characteristic impedance (Zc) and central pulse pressure positively trended with various platelet traits, while pulse wave velocity and Zc negatively trended with collagen, ADP, and epinephrine traits. All results did not pass a stringent multiple test correction threshold ( < 2.22e-04). The diameter trends were consistent with lower shear environments invoking less platelet reactivity. The vessel calcium trends were consistent with subclinical atherosclerosis and platelet activation being inter-related.
Topics: Female; Male; Humans; Calcium; Pulse Wave Analysis; Blood Pressure; Platelet Activation; Atherosclerosis
PubMed: 37609998
DOI: 10.1080/09537104.2023.2238835