Pericytes as targets in hereditary hemorrhagic telangiectasia

Thalgott, Jérémy H.; Dos-Santos-Luis, Damien; Lebrin, Franck

doi:10.3389/fgene.2015.00037

Cited by 48 publications

(40 citation statements)

References 162 publications

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“…40 Histologically, angiodys-plasia is associated with endothelial proliferation and pericyte loss. 3,4 Studies have suggested TNF-α/Ang-2 synergy leads to pericyte apoptosis. 13,41 Herein we found TNF-α–induced pericyte apoptosis in LVAD patients is associated with suppression of Ang-1, which is blunted by TNF-α blockade.…”

Section: Discussionmentioning

confidence: 99%

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Tumor necrosis factor-α levels and non-surgical bleeding in continuous-flow left ventricular assist devices

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Coplan

Chen

et al. 2018

The Journal of Heart and Lung Transplantation

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BACKGROUND Non-surgical bleeding (NSB) due to angiodysplasia is common in left ventricular assist device (LVAD) patients. Thrombin-induced angiopoietin-2 (Ang-2) expression in LVAD patients leads to altered angiogenesis and is associated with lower angiopoietin-1 (Ang-1) and increased NSB. However, the mechanism for decreased Ang-1, made by pericytes, is unknown and the origin of thrombin in LVAD patients is unclear. We hypothesized that high tumor necrosis factor-α (TNF-α) levels in LVAD patients induce pericyte apoptosis, tissue factor (TF) expression and vascular instability. METHODS We incubated cultured pericytes with serum from patients with heart failure (HF), LVAD or orthotopic heart transplantation (OHT), with or without TNF-α blockade. We performed several measurements: Ang-1 expression was assessed by reverse transcript-polymerase chain reaction (RT-PCR) and pericyte death fluorescently; TF expression was assessed by RT-PCR in cultured endothelial cells incubated with patient plasma with or without TNF-α blockade; and TF expression was assessed in endothelial biopsy samples from these patients by immunofluorescence. We incubated cultured endothelial cells on Matrigel with patient serum with or without TNF-α blockade and determined tube formation by microscopy. RESULTS Serum from LVAD patients had higher levels of TNF-α, suppressed Ang-1 expression in pericytes, and induced pericyte death, and there was accelerated endothelial tube formation compared with serum from patients without LVADs. TF was higher in both plasma and endothelial cells from LVAD patients, and plasma from LVAD patients induced more endothelial TF expression. All of these effects were reversed or reduced with TNF-α blockade. High levels of TNF-α were associated with increased risk of NSB. CONCLUSIONS Elevated TNF-α in LVAD patients is a central regulator of altered angiogenesis, pericyte apoptosis and expression of TF and Ang-1.

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Section: Discussionmentioning

confidence: 99%

“…1,2 However, the under-lying mechanism remains unknown. Angiodysplasia is associated with endothelial proliferation and decreased vessel coverage by pericytes, 3,4 non-endothelial vascular cells that support the endothelium. Pericytes produce angiopoietin-1 (Ang-1), an agonist of Tie-2, 5 which promotes vessel stability.…”

mentioning

confidence: 99%

Tumor necrosis factor-α levels and non-surgical bleeding in continuous-flow left ventricular assist devices

Tabit

Coplan

Chen

et al. 2018

The Journal of Heart and Lung Transplantation

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“…The endoglin, ALK1, and SMAD4 proteins are components of the transforming growth factor-β/bone morphogenetic protein signaling pathways: ALK1 is a type I transmembrane serine threonine receptor kinase, endoglin is an auxiliary receptor, and SMAD4 is the common partner for canonical (SMAD-based) signaling [5] . While the exact pathogenic mechanisms are yet to be determined, vascular abnormalities in HHT are thought to arise due to resultant imbalances in the response to angiogenic factors such as vascular endothelial growth factor [6] , defective vascular repair [7] , and/or modified vessel maturation [8] . Recently, heterozygous missense substitutions in the GDF2 gene, which encodes bone morphogenetic protein 9, have been reported in individuals with some cutaneous vascular lesions similar to those seen in HHT [9,10] , although the pathogenicity of the gene variants remains uncertain.…”

Section: Introductionmentioning

confidence: 99%

The Lung in Hereditary Hemorrhagic Telangiectasia

2017

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Hereditary hemorrhagic telangiectasia (HHT) is a dominantly inherited genetic vascular disorder with an estimated prevalence of 1 in 6,000, characterized by recurrent epistaxis, cutaneous telangiectasia, and arteriovenous malformations (AVMs) that affect many organs including the lungs, gastrointestinal tract, liver, and brain. Its diagnosis is based on the Curaçao criteria, and is considered definite if at least 3 of the 4 following criteria are fulfilled: (1) spontaneous and recurrent epistaxis, (2) telangiectasia, (3) a family history, and (4) pulmonary, liver, cerebral, spinal, or gastrointestinal AVMs. The focus of this review is on delineating how HHT affects the lung.

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“…Interestingly, this data adds to the growing body of evidence for a pleiotropic role of BMP9 in development and disease. While a defective paracrine signaling between endothelial cells and the neighboring mural cells may be one of the underlying causes of HHT (Thalgott et al., 2015), neutralization of BMP9 in tumor angiogenesis may lead to opposing effects, as indicated by increased numbers of pericyte covered tumor vessels.…”

Section: Discussionmentioning

confidence: 99%

Impact of selective anti‐BMP9 treatment on tumor cells and tumor angiogenesis

et al. 2016

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The role of bone morphogenic protein 9 (BMP9) signaling in angiogenesis has been controversial, with a number of studies showing that it acts either as a pro-angiogenic or, conversely, as an anti-angiogenic factor in a context-dependent manner. Notably, BMP9 was also reported to function in both pro- or anti-tumorigenic roles during tumor progression. It has therefore remained unclear, whether selective BMP9 inhibition is a useful target for antibody therapy of cancer. To shed light on these questions, we characterized BMP9 expression in plasma of patients with different cancer indications and found elevated levels of pro-domains and precursor BMP9 with a strong response in renal cell carcinoma (RCC). These studies prompted us to evaluate the potential of selective anti-BMP9 cancer therapy in RCC. We generated a novel monoclonal therapeutic antibody candidate, mAb BMP9-0093, that selectively targets all different BMP9 variants but does not bind to the closest homolog BMP10. In vitro, mAb BMP9-0093 treatment inhibited signaling, endothelin-1 (ET-1) production and spreading of endothelial cells and restored BMP9-induced decrease in pericyte migration and attachment. Furthermore, BMP9-mediated epithelial-mesenchymal transition of renal cell carcinoma cells was reversed by mAb BMP9-0093 treatment in vitro. In vivo, mAb BMP9-0093 showed significant anti-tumor activity that was associated with an increase in apoptosis as well as a decrease in tumor cell proliferation and ET-1 release. Furthermore, mAb BMP9-0093 induced mural cell coverage of endothelial cells, which was corroborated by a reduction in vascular permeability, demonstrated by a diminished penetration of omalizumab-Alexa 647 into tumor tissue. Our findings provide new evidence for a better understanding of BMP9 contribution in tumor progression and angiogenesis that may result in the development of effective targeted therapeutic interventions.

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Pericytes as targets in hereditary hemorrhagic telangiectasia

Cited by 48 publications

References 162 publications

Tumor necrosis factor-α levels and non-surgical bleeding in continuous-flow left ventricular assist devices

Tumor necrosis factor-α levels and non-surgical bleeding in continuous-flow left ventricular assist devices

The Lung in Hereditary Hemorrhagic Telangiectasia

Impact of selective anti‐BMP9 treatment on tumor cells and tumor angiogenesis

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