Reduced proliferation of endothelial colony-forming cells in unprovoked venous thromboembolic disease as a consequence of endothelial dysfunction

Abstract

BackgroundVenous thromboembolic disease (VTD) is a public health problem. We recently reported that endothelial colony-forming cells (ECFCs) derived from endothelial cells (EC) (ECFC-ECs) from patients with VTD have a dysfunctional state. For this study, we proposed that a dysfunctional status of these cells generates a reduction of its proliferative ability, which is also associated with senescence and reactive oxygen species (ROS).Methods and resultsHuman mononuclear cells (MNCs) were obtained from peripheral blood from 40 healthy human volunteers (controls) and 50 patients with VTD matched by age (20−50 years) and sex to obtain ECFCs. We assayed their proliferative ability with plasma of patients and controls and supernatants of cultures from ECFC-ECs, senescence-associated β-galactosidase (SA-β-gal), ROS, and expression of ephrin-B2/Eph-B4 receptor. Compared with cells from controls, cells from VTD patients showed an 8-fold increase of ECFCs that emerged 1 week earlier, reduced proliferation at long term (39%) and, in passages 4 and 10, a highly senescent rate (30±1.05% vs. 91.3±15.07%, respectively) with an increase of ROS and impaired expression of ephrin-B2/Eph-4 genes. Proliferation potential of cells from VTD patients was reduced in endothelial medium [1.4±0.22 doubling population (DP)], control plasma (1.18±0.31 DP), or plasma from VTD patients (1.65±0.27 DP).ConclusionsAs compared with controls, ECFC-ECs from individuals with VTD have higher oxidative stress, proliferation stress, cellular senescence, and low proliferative potential. These findings suggest that patients with a history of VTD are ECFC-ECs dysfunctional that could be associated to permanent risk for new thrombotic events.

Therapeutic Potential of Endothelial Colony-Forming Cells in Ischemic Disease: Strategies to Improve their Regenerative Efficacy

“…Third, ECFCs’ angiogenic behavior is typically compromised in the presence of cardiovascular risk factors that predispose to the onset of ischemic disorders; this further contributes to discouraging the use of circulating ECFCs for autologous cell therapy [ 15 , 59 , 110 , 115 ]. For instance, the frequency and/or vasoreparative potential of circulating ECFCs are remarkably reduced with CAD [ 120 ], aging [ 121 ], diabetes [ 122 ], abdominal aortic aneurysm [ 123 ], venous thromboembolic disease [ 124 ], congenital diaphragmatic hernia [ 125 ], systemic lupus erythematosus [ 126 ], and the pediatric Moyamoya disease (MMD) [ 127 ]. In addition, ECFCs’ angiogenic behaviour is impaired in patients affected by human immunodeficiency virus (HIV), which has long been associated with cardiovascular disorders [ 128 ].…”

Recent Advances in Endothelial Colony Forming Cells Toward Their Use in Clinical Translation

“…An increased pro-inflammatory cytokines profile was also found in the supernatants of cultures of ECFC from VTD patients ( 36 ). Further studies showed that ECFC from patients with VTD exhibit reduced proliferation, increased senescence, increased levels of reactive oxygen species (ROS) and impaired expression of ephrin-B2/Eph-4 genes, markers of venous and arterial endothelium involved in vascular regeneration ( 37 ). The abnormal inflammatory response, increased oxidative-stress and senescence detected in ECFC from patients with VTD might contribute to a defective response of the endothelium to vascular injury in these patients, possibly leading to recurrent thrombotic events.…”

Molecular and Clinical Issues about the Risk of Venous Thromboembolism in Older Patients: A Focus on Parkinson’s Disease and Parkinsonism

“…Furthermore, the authors found that ECFCs from VTE patients had an impaired ephrin-B2/Eph-4 gene transcription and enhanced oxidative stress with increased ROS, suggesting also a higher prothrombotic oxidation-related risk in these patient as compared to controls [ 33 ].…”