scholarly journals Autoantibodies Targeting AT1- and ETA-Receptors Link Endothelial Proliferation and Coagulation via Ets-1 Transcription Factor

2021 ◽  
Vol 23 (1) ◽  
pp. 244
Author(s):  
Rusan Catar ◽  
Melanie Herse-Naether ◽  
Nan Zhu ◽  
Philine Wagner ◽  
Oskar Wischnewski ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Transcription Factor ◽  
Endothelial Cell ◽  
Intracellular Signaling ◽  
Mapk Pathway ◽  
Vascular Complications ◽  
Receptor Activation ◽  
Endothelial Cell Proliferation ◽  
Scleroderma Renal Crisis ◽  
Endothelial Proliferation

Scleroderma renal crisis (SRC) is an acute life-threatening manifestation of systemic sclerosis (SSc) caused by obliterative vasculopathy and thrombotic microangiopathy. Evidence suggests a pathogenic role of immunoglobulin G (IgG) targeting G-protein coupled receptors (GPCR). We therefore dissected SRC-associated vascular obliteration and investigated the specific effects of patient-derived IgG directed against angiotensin II type 1 (AT1R) and endothelin-1 type A receptors (ETAR) on downstream signaling events and endothelial cell proliferation. SRC-IgG triggered endothelial cell proliferation via activation of the mitogen-activated protein kinase (MAPK) pathway and subsequent activation of the E26 transformation-specific-1 transcription factor (Ets-1). Either AT1R or ETAR receptor inhibitors/shRNA abrogated endothelial proliferation, confirming receptor activation and Ets-1 signaling involvement. Binding of Ets-1 to the tissue factor (TF) promoter exclusively induced TF. In addition, TF inhibition prevented endothelial cell proliferation. Thus, our data revealed a thus far unknown link between SRC-IgG-induced intracellular signaling, endothelial cell proliferation and active coagulation in the context of obliterative vasculopathy and SRC. Patients’ autoantibodies and their molecular effectors represent new therapeutic targets to address severe vascular complications in SSc.

Notch2 Suppression Mimicking Changes in Human Pulmonary Hypertension Modulates Notch1 and Promotes Endothelial Cell Proliferation

2021 ◽  
Author(s):  
Sanghamitra Sahoo ◽  
Yao Li ◽  
Daniel de Jesus ◽  
John Charles Sembrat II ◽  
Mauricio M Rojas ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Endothelial Cells ◽  
Endothelial Cell ◽  
Target Genes ◽  
Pulmonary Arteries ◽  
Notch Receptor ◽  
Endothelial Cell Proliferation ◽  
Tissue Samples ◽  
Endothelial Proliferation ◽  
Human Pulmonary Artery

Pulmonary arterial hypertension (PAH) is a fatal cardiopulmonary disease characterized by increased vascular cell proliferation with resistance to apoptosis and occlusive remodeling of the small pulmonary arteries in humans. The Notch family of proteins are proximal signaling mediators of an evolutionarily conserved pathway that effect cell proliferation, fate determination, and development. In endothelial cells (ECs), Notch receptor 2 (Notch2) has been shown to promote endothelial apoptosis. However, a pro- or anti-proliferative role for Notch2 in pulmonary endothelial proliferation and ensuing PAH is unknown. Herein, we postulated that suppressed Notch2 signaling drives pulmonary endothelial proliferation in the setting of PAH. We observed that levels of Notch2 are ablated in lung and PA tissue samples from PAH patients compared to non-PAH controls. Interestingly, Notch2 expression was attenuated in human pulmonary artery endothelial cells (hPAECs) exposed to vasoactive factors including hypoxia, TGFβ, ET-1, and IGF-1. Gene silencing of Notch2 increased EC proliferation and reduced apoptosis. At the molecular level, Notch2-deficient hPAECs activated Akt, Erk1/2 and anti-apoptotic protein Bcl-2, and reduced levels of p21cip and Bax. Intriguingly, loss of Notch2 elicits a paradoxical activation of Notch1 and transcriptional upregulation of canonical Notch target genes Hes1, Hey1 and Hey2. Further, reduction in Rb and increased E2F1 binding to the Notch1 promoter appear to explain the upregulation of Notch1. In aggregate, our results demonstrate that loss of Notch2 derepresses Notch1 and elicits aberrant EC hallmarks of PAH. The data underscore a novel role for Notch in the maintenance of endothelial cell homeostasis.

Abstract P248: Novel Role of Axl Kinase in Endothelial Cell Proliferation and Pulmonary Arterial Hypertension

Hypertension ◽  
2017 ◽  
Vol 70 (suppl_1) ◽  
Author(s):  
Anastasia Gorelova ◽  
Sanghamitra Sahoo ◽  
Patrick J Pagano
Keyword(s):  
Cell Proliferation ◽  
Endothelial Cell ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Endothelial Cell Proliferation ◽  
Vegf Receptor ◽  
Drug Bioavailability ◽  
Endothelial Proliferation ◽  
Pulmonary Arterial

Pulmonary arterial hypertension (PAH) is a poorly characterized disease of unclear etiology that affects individuals of all ages. Vascular remodeling and increase in pulmonary artery (PA) and right ventricle (RV) pressures are two major culprits in RV failure and death in PAH. Recent advances in the study of PAH suggest that endothelial cell proliferation is an early instigator of this hallmark remodeling. We postulated that Axl receptor tyrosine kinase (implicated in pro-proliferative and pro-survival signaling in cancerous cells) could mediate endothelial proliferation and thus hemodynamic changes occurring in PAH. Using immunofluorescent microscopy of lung microvessels of human PAH vs. non-PAH, we observed Axl expression on intimal endothelial cells but not medial smooth muscle cells. Furthermore, digitized microscopy revealed that Axl tended to increase on the endothelium of PAH vessels (1.65±0.15-fold vs. non-PAH; n=3-4; p=0.057 ). To address the role of Axl in vivo , an Axl inhibitor R428 was employed in a mouse model of pulmonary hypertension. C57Bl/6 mice were subjected to hypoxia at pO 2 =10% and VEGF receptor antagonist SU5416 (Su/Ch) or normoxia (Norm) for 3 wks. Indeed, Su/Ch caused a significant rise in lung Axl protein and mRNA (7.1±0.4- and 2.4±0.5-fold, Su/Ch vs. Norm, protein and mRNA, respectively; n=3-6; p<0.01). As predicted, RV pressure (RVP) rose from 27±0.5 to 43±1.8 mmHg (Norm vs. Su/Ch; n=6; p<0.01). However, we did not observe a decrease in RVP with twice-daily gavage of 75 mg/kg R428 (43±1.4 mmHg, Su/Ch + R428; n=6). A similar pattern was observed with mean PA pressure (18.4±0.3 and 28.7±1.2 mmHg, Norm vs. Su/Ch, p<0.01; 28.7±0.9 mmHg, Su/Ch + R428), RV resistance (1403±256 vs. 2703±464 Wood units, Norm vs. Su/Ch, n/s; vs. 3610±625 Wood units, Su/Ch + R428) and Fulton index (0.26±0.01 and 0.34±0.02, Norm vs. Su/Ch, p<0.05; 0.38±0.02, Su/Ch + R428). In conclusion, our preliminary results demonstrate upregulated Axl expression in the endothelium of PAH patients and in lungs of PH mice and suggest that Axl kinase may play a novel role in pulmonary vascular endothelial proliferation and remodeling in PAH. It remains to be determined whether drug bioavailability or severity of disease precluded an ameliorative effect of an Axl inhibitor.

Combined effect of bradykinin B 2 and neurokinin‐1 receptor activation on endothelial cell proliferation in acute synovitis.

2004 ◽  
Vol 18 (6) ◽  
pp. 762-764 ◽  
Author(s):  
Hélène C. Seegers ◽  
Paul S. Avery ◽  
Daniel F. McWilliams ◽  
Lyane Haywood ◽  
David A. Walsh
Keyword(s):  
Cell Proliferation ◽  
Endothelial Cell ◽  
Receptor Activation ◽  
Combined Effect ◽  
Endothelial Cell Proliferation ◽  
Neurokinin 1 Receptor ◽  
Neurokinin 1

scholarly journals Cell Cycle-dependent Phosphorylation of the RUNX2 Transcription Factor by cdc2 Regulates Endothelial Cell Proliferation

2006 ◽  
Vol 281 (11) ◽  
pp. 7118-7128 ◽  
Author(s):  
Meng Qiao ◽  
Paul Shapiro ◽  
Matthew Fosbrink ◽  
Horea Rus ◽  
Rakesh Kumar ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Transcription Factor ◽  
Endothelial Cell ◽  
Endothelial Cell Proliferation ◽  
Cycle Dependent
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