Angiopoietin-2 Secretion by Endothelial Cell Exosomes

Ju, Rong; Zhuang, Zhen W.; Zhang, Jiasheng; Lanahan, Anthony A.; Kyriakides, Themis R.; Sessa, William C.; Simons, Michael

doi:10.1074/jbc.m113.506899

Cited by 90 publications

(39 citation statements)

References 34 publications

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“…12, 36 PAR-1 activates the Phospholipase-C-β signaling cascade, inducing Weibel-Palade Body exocytosis and Ang-2 expression. 15, 37 In line with this mechanism, our findings implicate thrombin-induced PAR-1 activation as the most likely mechanism for the increased Ang-2 found in patients with LVADs. The further increase in Ang-2 levels in patients with HVADs is of unclear significance and may represent device-specific factors or patient specific factors as all patients in our study with an HVAD received the device as part of a bridge-to-transplant (BTT) strategy while patients with a Heartmate II used as BTT or destination therapy were studied.…”

Section: Discussionsupporting

confidence: 77%

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Elevated Angiopoietin-2 Level in Patients With Continuous-Flow Left Ventricular Assist Devices Leads to Altered Angiogenesis and Is Associated With Higher Nonsurgical Bleeding

et al. 2016

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Background Non-surgical bleeding (NSB) is the most common adverse event in patients with continuous-flow left ventricular assist devices (LVADs) and is caused by arteriovenous malformations (AVMs). We hypothesized that deregulation of an angiogenic factor, Angiopoietin-2 (Ang-2), in LVAD patients leads to increased angiogenesis and higher NSB. Methods Ang-2 and thrombin levels were measured by ELISA and Western blotting, respectively, in blood samples from 101 patients with heart failure (HF), LVAD, or orthotopic heart transplant (OHT). Ang-2 expression in endothelial biopsy was quantified by immunofluorescence. Angiogenesis was determined by in vitro tube formation using serum from each patient with or without Ang-2-blocking antibody. Ang-2 gene expression was measured by RT-PCR in endothelial cells incubated with plasma from each patient with or without the thrombin receptor blocker Vorapaxar. Results Compared with HF or OHT patients, serum levels and endothelial expression of Ang-2 were higher in LVAD patients (p=0.001 and p<0.001, respectively). This corresponded with increased angiogenic potential of serum from patients with LVADs (p<0.001), which was normalized with Ang-2 blockade. Furthermore, plasma from LVAD patients contained higher amounts of thrombin (p=0.003) which was associated with activation of the contact coagulation system. Plasma from LVAD patients induced more Ang-2 gene expression in endothelial cells (p<0.001) which was reduced with thrombin receptor blockade (p=0.013). LVAD patients with Ang-2 levels above the mean (12.32 ng/mL) had more NSB events compared with patients with Ang-2 levels below the mean (p=0.003). Conclusions Our findings indicate that thrombin-induced Ang-2 expression in LVAD patients leads to increased angiogenesis in vitro and may be associated with higher NSB events. Ang-2 therefore may contribute to AVM formation and subsequent bleeding in LVAD patients.

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Section: Discussionsupporting

confidence: 77%

“…11–15 Prior studies have suggested that plasma levels of thrombin may be elevated in patients with LVADs. 16–18 Given the known relationship between thrombin-dependent PAR-1 activation and Ang-2 expression and release, we hypothesized that thrombin-induced Ang-2 overexpression in patients with LVADs may promote altered blood vessel growth.…”

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confidence: 99%

Elevated Angiopoietin-2 Level in Patients With Continuous-Flow Left Ventricular Assist Devices Leads to Altered Angiogenesis and Is Associated With Higher Nonsurgical Bleeding

et al. 2016

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“…Filling the gaps of our understanding is imperative if we want to eventually be able to modulate this process in different cell types and diseases. Many different cells are capable of secreting both exosomes and MVs, including red blood cells[15] platelets[16], lymphocytes[17], dendritic cells[18], fibroblasts[19], endothelial cells[20], and epithelial and tumor cells[21]. Recent reports suggest that different types of EVs can originate from the same donor cells, and whether the various biogenetic pathways are completely independent or overlapping, and to what extent, needs further study[22].…”

Section: Exosomes and Microvesiclesmentioning

confidence: 99%

Extracellular Vesicles in Cancer: Exosomes, Microvesicles and the Emerging Role of Large Oncosomes

Minciacchi

Freeman

Vizio

2015

Seminars in Cell & Developmental Biology

773

638

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Since their first description, extracellular vesicles (EVs) have been the topic of avid study in a variety of physiologic contexts and are now thought to play an important role in cancer. The state of knowledge on biogenesis, molecular content and horizontal communication of diverse types of cancer EVs has expanded considerably in recent years. As a consequence, a plethora of information about EV composition and molecular pathways involved in the regulation of important biological processes has emerged, along with the notion that cancer cells rely on these particles to invade tissues and propagate oncogenic signals at distance. In vivo studies, designed to achieve a deeper understanding of the extent to which EV biology can be applied to clinically relevant settings, are increasing. This review will summarize recent studies on EVs functionally implicated in cancer, with a focus on a novel EV population referred to as large oncosomes, which originate from highly migratory, amoeboid tumor cells. Here we provide an overview about the biogenesis and composition of exosomes, microvesicles and large oncosomes, along with their cancer-specific and more general functions. We also discuss current challenges and emerging technologies that might improve EV detection in various systems. Further studies on the functional role of EVs in specific steps of cancer formation and progression will expand our understanding of the diversity of paracrine signaling mechanisms in malignant growth.

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“…A recent study demonstrated that excessive Ang2 secretion could be rescued by syndecan-4 knockout or syntenin inhibition. Notably, knockdown of MDA-9/Syntenin, which can bind all syndecans, had a larger reductive effect in Ang2 secretion than single syndecan knockdown [109]. MDA-9/Syntenin was found to be significantly elevated in the plasma of diabetic patients compared to healthy donors as well as upregulated in liver cells cultured in high-glucose media [110].…”

Section: Angiogenesis and Inflammationmentioning

confidence: 99%

Targeting tumor invasion: the roles of MDA-9/Syntenin

Kegelman

Das

Emdad

et al. 2014

Expert Opinion on Therapeutic Targets

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Introduction Melanoma differentiation-associated gene – 9 (MDA-9)/Syntenin has become an increasingly popular focus for investigation in numerous cancertypes. Originally implicated in melanoma metastasis, it has diverse cellular roles and is consistently identified as a regulator of tumor invasion and angiogenesis. As a potential target for inhibiting some of the most lethal aspects of cancer progression, further insight into the function of MDA-9/Syntenin is mandatory. Areas covered Recent literature and seminal articles were reviewed to summarize the latest collective understanding of MDA-9/Syntenin’s role in normal and cancerous settings. Insights into its participation in developmental processes are included, as is the functional significance of the N- and C-terminals and PDZ domains of MDA-9/Syntenin. Current reports highlight the clinical significance of MDA-9/Syntenin expression level in a variety of cancers, often correlating directly with reduced patient survival. Also presented are assessments of roles of MDA-9/Syntenin in cancer progression as well as its functions as an intracellular adapter molecule. Expert opinion Multiple studies demonstrate the importance of MDA-9/ Syntenin in tumor invasion and progression. Through the use of novel drug design approaches, this protein may provide a worthwhile therapeutic target. As many conventional therapies do not address, or even enhance, tumor invasion, an anti-invasive approach would be a worthwhile addition in cancer therapy.

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Angiopoietin-2 Secretion by Endothelial Cell Exosomes

Cited by 90 publications

References 34 publications

Elevated Angiopoietin-2 Level in Patients With Continuous-Flow Left Ventricular Assist Devices Leads to Altered Angiogenesis and Is Associated With Higher Nonsurgical Bleeding

Elevated Angiopoietin-2 Level in Patients With Continuous-Flow Left Ventricular Assist Devices Leads to Altered Angiogenesis and Is Associated With Higher Nonsurgical Bleeding

Extracellular Vesicles in Cancer: Exosomes, Microvesicles and the Emerging Role of Large Oncosomes

Targeting tumor invasion: the roles of MDA-9/Syntenin

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