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Stem Cell Research & Therapy May 2021Maintaining the stability and maturation of blood vessels is of paramount importance for the vessels to carry out their physiological function. Smooth muscle cells...
BACKGROUND
Maintaining the stability and maturation of blood vessels is of paramount importance for the vessels to carry out their physiological function. Smooth muscle cells (SMCs), pericytes, and mesenchymal stem cells (MSCs) are involved in the maturation process of the newly formed vessels. The aim of this study was to investigate whether transforming growth factor beta 1 (TGF-β1) treatment could enhance pericyte-like properties of dental pulp stem cells (DPSCs) and how TGF-β1-treated DPSCs for 7 days (T-DPSCs) stabilize the newly formed blood vessels.
METHODS
We utilized TGF-β1 to treat DPSCs for 1, 3, 5, and 7 days. Western blotting and immunofluorescence were used to analyze the expression of SMC markers. Functional contraction assay was conducted to assess the contractility of T-DPSCs. The effects of T-DPSC-conditioned media (T-DPSC-CM) on human umbilical vein endothelial cell (HUVEC) proliferation and migration were examined by MTT, wound healing, and trans-well migration assay. Most importantly, in vitro 3D co-culture spheroidal sprouting assay was used to investigate the regulating role of vascular endothelial growth factor (VEGF)-angiopoietin (Ang)-Tie2 signaling on angiogenic sprouting in 3D co-cultured spheroids of HUVECs and T-DPSCs. Angiopoietin 2 (Ang2) and VEGF were used to treat the co-cultured spheroids to explore their roles in angiogenic sprouting. Inhibitors for Tie2 and VEGFR2 were used to block Ang1/Tie2 and VFGF/VEGFR2 signaling.
RESULTS
Western blotting and immunofluorescence showed that the expression of SMC-specific markers (α-SMA and SM22α) were significantly increased after treatment with TGF-β1. Contractility of T-DPSCs was greater compared with that of DPSCs. T-DPSC-CM inhibited HUVEC migration. In vitro sprouting assay demonstrated that T-DPSCs enclosed HUVECs, resembling pericyte-like cells. Compared to co-culture with DPSCs, a smaller number of HUVEC sprouting was observed when co-cultured with T-DPSCs. VEGF and Ang2 co-stimulation significantly enhanced sprouting in HUVEC and T-DPSC co-culture spheroids, whereas VEGF or Ang2 alone exerted insignificant effects on HUVEC sprouting. Blocking Tie2 signaling reversed the sprouting inhibition by T-DPSCs, while blocking VEGF receptor (VEGFR) signaling boosted the sprouting inhibition by T-DPSCs.
CONCLUSIONS
This study revealed that TGF-β1 can induce DPSC differentiation into functional pericyte-like cells. T-DPSCs maintain vessel stability through Ang1/Tie2 and VEGF/VEGFR2 signaling.
Topics: Angiopoietins; Coculture Techniques; Humans; Neovascularization, Physiologic; Transforming Growth Factor beta1; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors
PubMed: 33971955
DOI: 10.1186/s13287-021-02349-y -
Ophthalmology Aug 2019The phase 2 BOULEVARD trial compared safety and efficacy of faricimab, a novel bispecific antibody targeting angiopoietin-2 and vascular endothelial growth factor-A... (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
The phase 2 BOULEVARD trial compared safety and efficacy of faricimab, a novel bispecific antibody targeting angiopoietin-2 and vascular endothelial growth factor-A (VEGF-A), with ranibizumab in patients with diabetic macular edema (DME).
DESIGN
The BOULEVARD trial (ClinicalTrials.gov identifier, NCT02699450) was a prospective, randomized, active comparator-controlled, double-masked, multicenter, phase 2 study conducted at 59 sites in the United States.
PARTICIPANTS
The trial enrolled patients 18 years of age or older with center-involving DME, best-corrected visual acuity (BCVA) of 73 to 24 Early Treatment Diabetic Retinopathy Study (ETDRS) letters, and central subfield thickness (CST) of 325 μm or more.
METHODS
Anti-VEGF treatment-naïve patients were randomized 1:1:1 to intravitreal 6.0 mg faricimab, 1.5 mg faricimab, or 0.3 mg ranibizumab, and patients previously treated with anti-VEGF were randomized 1:1 to 6.0 mg faricimab or 0.3 mg ranibizumab. Patients were dosed monthly for 20 weeks, followed by an observation period up to week 36 to assess durability.
MAIN OUTCOME MEASURES
The prespecified primary outcome measure was mean change in BCVA from baseline at week 24 for faricimab versus ranibizumab in treatment-naïve patients. Key secondary and exploratory outcome measures included CST, Diabetic Retinopathy Severity Scale (DRSS) score, and durability as assessed by time to re-treatment.
RESULTS
The trial enrolled 229 patients (168 treatment-naïve and 61 previously treated with anti-VEGF). In treatment-naïve patients, 6.0 mg faricimab, 1.5 mg faricimab, and 0.3 mg ranibizumab resulted in mean improvements of 13.9, 11.7, and 10.3 ETDRS letters from baseline, respectively. The 6.0-mg faricimab dose demonstrated a statistically significant gain of 3.6 letters over ranibizumab (P = 0.03). In both patient populations, faricimab resulted in dose-dependent reductions in CST, improvements in DRSS score, and longer time to re-treatment during the observation period compared with ranibizumab. Faricimab showed no new or unexpected safety signals.
CONCLUSIONS
The BOULEVARD trial met its primary end point; faricimab demonstrated statistically superior visual acuity gains versus ranibizumab at week 24 in treatment-naïve patients. Central subfield thickness reduction, DRSS score improvement, and extended durability outcomes support the primary outcome. These findings suggest the benefit of simultaneous inhibition of angiopoietin-2 and VEGF-A with faricimab for patients with DME.
Topics: Adult; Aged; Aged, 80 and over; Angiogenesis Inhibitors; Angiopoietin-2; Antibodies, Monoclonal; Diabetic Retinopathy; Female; Humans; Intravitreal Injections; Macular Edema; Male; Middle Aged; Ranibizumab; Vascular Endothelial Growth Factor A
PubMed: 30905643
DOI: 10.1016/j.ophtha.2019.03.023 -
Cells Oct 2020Due to the usually late diagnosis and lack of effective therapies, hepatocellular carcinoma (HCC), which poses a growing global health problem, is characterized by a... (Review)
Review
Due to the usually late diagnosis and lack of effective therapies, hepatocellular carcinoma (HCC), which poses a growing global health problem, is characterized by a poor prognosis. Angiogenesis plays an important role in HCC progression, and vascular endothelial growth factor (VEGF) and angiopoietins (Angs) are key drivers of HCC angiogenesis. VEGF-targeting strategies already represent an important component of today's systemic treatment landscape of HCC, whereas targeting the Ang/Tie2 signaling pathway may harbor future potential in this context due to reported beneficial anticancer effects when targeting this pathway. In addition, a better understanding of the relation between Angs and HCC angiogenesis and progression may reveal their potential as predictive factors for post-treatment disease progression and prognosis. In this review, we give a comprehensive overview of the complex role of Ang/Tie2 signaling in HCC, pinpointing its potential value as biomarker and target for HCC treatments, aiding HCC diagnosis and therapy.
Topics: Angiopoietins; Carcinoma, Hepatocellular; Humans; Liver Neoplasms; Neovascularization, Pathologic; Receptor, TIE-2; Signal Transduction; Vascular Remodeling
PubMed: 33143149
DOI: 10.3390/cells9112382 -
Cell Death & Disease Aug 2022Angiogenesis is considered as an important process in tumor growth, metastasis of hepatocellular carcinoma (HCC) and associated with cancer progression, suggesting that...
Angiogenesis is considered as an important process in tumor growth, metastasis of hepatocellular carcinoma (HCC) and associated with cancer progression, suggesting that an important research and development field of clinical molecular targeted drugs for HCC. However, the molecular mechanisms underlying tumor angiogenesis in HCC remains elusive. In the current study, we demonstrate that upregulation of AMYB proto-oncogene-like 1 (MYBL1) was associated with high endothelial vessel (EV) density and contributed to poor prognosis of HCC patient. Functionally, MYBL1 overexpressing enhanced the capacity of HCC cells to induce tube formation, migration of HUVECs, neovascularization in CAMs, finally, enhanced HCC cells metastasis, while silencing MYBL1 had the converse effect. Furthermore, HCC cells with high MYBL1 expression were more resistance to sorafenib treatment. We observed that CD31 staining was significantly increased in tumors formed by MYBL1-overexpressing cells but decreased in MYBL1-silenced tumors. Mechanistically, MYBL1 binds to the ANGPT2 promoter and transcriptionally upregulate ANGPT2 mRNA expression. Strikingly, treatment with monoclonal antibody against ANGPT2 significantly inhibited the growth of MYBL1-overexpressing tumors and efficiently impaired angiogenesis. Furthermore, the histone post-translational factors: protein arginine methyltransferase 5 (PRMT5), MEP50, and WDR5 were required for MYBL1-mediated ANGPT2 upregulation. Importantly, we confirmed the correlation between MYBL1 and ANGPT2 expression in a large cohort of clinical HCC samples and several published datasets in pancreatic cancer, esophageal carcinoma, stomach adenocarcinoma, and colon cancer. Our results demonstrate that MYBL1 upregulated the ANGPT2 expression, then induced angiogenesis and confer sorafenib resistance to HCC cells, and MYBL1 may represent a novel prognostic biomarker and therapeutic target for patients with HCC.
Topics: Adaptor Proteins, Signal Transducing; Angiopoietin-2; Carcinoma, Hepatocellular; Cell Line, Tumor; Cell Proliferation; Drug Resistance, Neoplasm; Gene Expression Regulation, Neoplastic; Humans; Intracellular Signaling Peptides and Proteins; Liver Neoplasms; Neovascularization, Pathologic; Protein-Arginine N-Methyltransferases; Proto-Oncogene Proteins; Sorafenib; Trans-Activators; Transcriptional Activation
PubMed: 35987690
DOI: 10.1038/s41419-022-05180-2 -
The Journal of Experimental Medicine Jan 2023Primary tumors and distant site metastases form a bidirectionally communicating system. Yet, the molecular mechanisms of this crosstalk are poorly understood. Here, we...
Primary tumors and distant site metastases form a bidirectionally communicating system. Yet, the molecular mechanisms of this crosstalk are poorly understood. Here, we identified the proteolytically cleaved fragments of angiopoietin-like 4 (ANGPTL4) as contextually active protumorigenic and antitumorigenic contributors in this communication ecosystem. Preclinical studies in multiple tumor models revealed that the C-terminal fragment (cANGPTL4) promoted tumor growth and metastasis. In contrast, the N-terminal fragment of ANGPTL4 (nANGPTL4) inhibited metastasis and enhanced overall survival in a postsurgical metastasis model by inhibiting WNT signaling and reducing vascularity at the metastatic site. Tracing ANGPTL4 and its fragments in tumor patients detected full-length ANGPTL4 primarily in tumor tissues, whereas nANGPTL4 predominated in systemic circulation and correlated inversely with disease progression. The study highlights the spatial context of the proteolytic cleavage-dependent pro- and antitumorigenic functions of ANGPTL4 and identifies and validates nANGPTL4 as a novel biomarker of tumor progression and antimetastatic therapeutic agent.
Topics: Humans; Angiopoietin-Like Protein 4; Angiopoietins; Biomarkers, Tumor; Neoplasms; Peptide Fragments
PubMed: 36269299
DOI: 10.1084/jem.20202595 -
Current Atherosclerosis Reports Feb 2020Atherosclerosis is characterized by accumulation of lipids and chronic inflammation in medium size to large arteries. Recently, RNA-based antisense oligonucleotides... (Review)
Review
PURPOSE OF REVIEW
Atherosclerosis is characterized by accumulation of lipids and chronic inflammation in medium size to large arteries. Recently, RNA-based antisense oligonucleotides (ASOs) and small interfering RNAs (siRNAs) are being developed, along with small molecule-based drugs and monoclonal antibodies, for the treatment of risk factors associated with atherosclerosis.. The purpose of this review is to describe nucleic acid-based therapeutics and introduce novel RNAs that might become future tools for treatment of atherosclerosis.
RECENT FINDINGS
RNA-based inhibitors for PCSK9, Lp(a), ApoCIII, and ANGPTL3 have been successfully tested in phase II-III clinical trials. Moreover, multiple microRNA and long non-coding RNAs have been found to reduce atherogenesis in preclinical animal models. Clinical trials especially with ASOs and siRNAs directed to liver, targeting cholesterol and lipoprotein metabolism, have shown promising results. Additional research in larger patient cohorts is needed to fully evaluate the therapeutic potential of these new drugs.
Topics: Angiopoietin-Like Protein 3; Angiopoietin-like Proteins; Animals; Anticholesteremic Agents; Apolipoprotein C-III; Atherosclerosis; Humans; Lipoprotein(a); Liver; MicroRNAs; Oligonucleotides, Antisense; PCSK9 Inhibitors; RNA, Long Noncoding; RNA, Small Interfering
PubMed: 32034521
DOI: 10.1007/s11883-020-0826-2 -
Scientific Reports Jun 2023Primary open angle glaucoma (POAG) is a chronic, adult-onset optic neuropathy associated with characteristic optic disc and/or visual field changes. With a view to...
Primary open angle glaucoma (POAG) is a chronic, adult-onset optic neuropathy associated with characteristic optic disc and/or visual field changes. With a view to identifying modifiable risk factors for this common neurodegenerative condition, we performed a 'phenome-wide' univariable Mendelian randomisation (MR) study that involved analysing the relationship between 9661 traits and POAG. Utilised analytical approaches included weighted mode based estimation, the weighted median method, the MR Egger method and the inverse variance weighted (IVW) approach. Eleven traits related to POAG risk were identified including: serum levels of the angiopoietin-1 receptor (OR [odds ratio] = 1.11, IVW p = 2.34E-06) and the cadherin 5 protein (OR = 1.06, IVW p = 1.31E-06); intraocular pressure (OR = 2.46-3.79, IVW p = 8.94E-44-3.00E-27); diabetes (OR = 5.17, beta = 1.64, IVW p = 9.68E-04); and waist circumference (OR = 0.79, IVW p = 1.66E-05). Future research focussing on the effects of adiposity, cadherin 5 and angiopoietin-1 receptor on POAG development and progression is expected to provide key insights that might inform the provision of lifestyle modification advice and/or the development of novel therapies.
Topics: Adult; Humans; Angiopoietin-1; Glaucoma, Open-Angle; Causality; Phenomics; Phenotype; Mendelian Randomization Analysis; Genome-Wide Association Study; Polymorphism, Single Nucleotide
PubMed: 37340071
DOI: 10.1038/s41598-023-37144-7 -
Kidney Diseases (Basel, Switzerland) May 2023Angiopoietins (Ang) are essential angiogenic factors involved in angiogenesis, vascular maturation, and inflammation. The most studied angiopoietins, angiopoietin-1... (Review)
Review
BACKGROUND
Angiopoietins (Ang) are essential angiogenic factors involved in angiogenesis, vascular maturation, and inflammation. The most studied angiopoietins, angiopoietin-1 (Ang-1) and angiopoietin-2 (Ang-2), behave antagonistically to each other in vivo to sustain vascular endothelium homeostasis. While Ang-1 typically acts as the endothelium-protective mediator, its context-dependent antagonist Ang-2 can promote endothelium permeability and vascular destabilization, hence contributing to a poor outcome in vascular diseases via endothelial injury, vascular dysfunction, and microinflammation. The pathogenesis of kidney diseases is associated with endothelial dysfunction and chronic inflammation in renal diseases.
SUMMARY
Several preclinical studies report overexpression of Ang-2 in renal tissues of certain kidney disease models; additionally, clinical studies show increased levels of circulating Ang-2 in the course of chronic kidney disease, implying that Ang-2 may serve as a useful biomarker in these patients. However, the exact mechanisms of Ang-2 action in renal diseases remain unclear.
KEY MESSAGES
We summarized the recent findings on Ang-2 in kidney diseases, including preclinical studies and clinical studies, aiming to provide a systematic understanding of the role of Ang-2 in these diseases.
PubMed: 38306230
DOI: 10.1159/000529774 -
International Journal of Molecular... Oct 2022Port-wine stains (PWSs) are congenital vascular malformations that involve the skin and mucosa. To date, the mechanisms underlying the pathogenesis and progression of... (Review)
Review
Port-wine stains (PWSs) are congenital vascular malformations that involve the skin and mucosa. To date, the mechanisms underlying the pathogenesis and progression of PWSs are yet to be clearly elucidated. The potential reasons for dilated vessels are as follows: (1) somatic (R183Q) mutations that form enlarged capillary malformation-like vessels through angiopoietin-2, (2) decreased perivascular nerve elements, (3) the coexistence of Eph receptor B1 and ephrin B2, and (4) the deficiency of αSMA expression in pericytes. In addition, ERK, c-JNK, P70S6K, AKT, PI3K, and PKC are assumed to be involved in PWS development. Although pulsed-dye laser (PDL) remains the gold standard for treating PWSs, the recurrence rate is high. Topical drugs, including imiquimod, axitinib, and rapamycin, combined with PDL treatments, are expected to alter the recurrence rate and reduce the number of PDL sessions for PWSs. For the deep vascular plexus, photosensitizers or photothermal transduction agents encapsulated by nanocarriers conjugated to surface markers (CD133/CD166/VEGFR-2) possess a promising therapeutic potential in photodynamic therapy or photothermal therapy for PWSs. The pathogenesis, progression, and treatment of PWSs should be extensively investigated.
Topics: Humans; Port-Wine Stain; Ribosomal Protein S6 Kinases, 70-kDa; Vascular Endothelial Growth Factor Receptor-2; Angiopoietin-2; Imiquimod; Photosensitizing Agents; Ephrin-B2; Axitinib; Proto-Oncogene Proteins c-akt; Receptor, EphA1; Sirolimus; Phosphatidylinositol 3-Kinases; Treatment Outcome
PubMed: 36292993
DOI: 10.3390/ijms232012139 -
Frontiers in Immunology 2022Angiopoietin-2 (Ang2), a member of the angiopoietin family, is widely involved in the process of vascular physiology, bone physiology, adipose tissue physiology and the... (Review)
Review
Angiopoietin-2 (Ang2), a member of the angiopoietin family, is widely involved in the process of vascular physiology, bone physiology, adipose tissue physiology and the occurrence and development of inflammation, cardiac hypertrophy, rheumatoid, tumor and other diseases under pathological conditions. Proliferation and metastasis of cancer largely depend on angiogenesis. Therefore, anti-angiogenesis has become the target of tumor therapy. Due to the Ang2 plays a key role in promoting angiogenesis and stability in vascular physiology, the imbalance of its expression is an important condition for the occurrence and development of cancer. It has been proved that blocking Ang2 can inhibit the growth, invasion and metastasis of cancer cells. In recent years, research has been constantly supplemented. We focus on the mechanisms that regulate the expression of Ang2 mRNA and protein levels in different cancers, contributing to a better understanding of how Ang2 exerts different effects in different cancers and stages, as well as facilitating more specific targeting of relevant molecules in cancer therapy. At the same time, the importance of Ang2 in cancer growth, metastasis, prognosis and combination therapy is pointed out. And finally, we will discuss the current investigations and future challenges of combining Ang2 inhibition with chemotherapy, immunotherapy, and radiotherapy to increase its efficacy in cancer patients. This review provides a theoretical reference for the development of new targets and effective combination therapy strategies for cancer treatment in the future.
Topics: Angiopoietin-2; Humans; Neoplasms; Neovascularization, Pathologic; RNA, Messenger
PubMed: 35874764
DOI: 10.3389/fimmu.2022.949553