Serum from Varicose Patients Induces Senescence‐Related Dysfunction of Vascular Endothelium Generating Local and Systemic Proinflammatory Conditions

Abstract

Although the role of endothelium in varicose vein development is indisputable, the effect of the pathology on biological properties of endothelial cells remains unclear. Here we examined if the presence of varicose veins affects senescence of endothelial cells (HUVECs) and, if so, what will be the local and systemic outcome of this effect. Experiments showed that HUVECs subjected to serum from varicose patients display improved proliferation, increased expression of senescence marker, SA-β-Gal, and increased generation of reactive oxygen species (ROS), as compared with serum from healthy donors. Both increased SA-β-Gal activity and ROS release were mediated by TGF-β1, the concentration of which in varicose serum was elevated and the activity of which in vitro was prevented using specific neutralizing antibody. Senescent HUVECs exposed to varicose serum generated increased amounts of ICAM-1, VCAM-1, P-selectin, uPA, PAI-1, and ET-1. Direct comparison of sera from varicose and healthy donors showed that pathological serum contained increased level of ICAM-1, VCAM-1, P-selectin, uPA, and ET-1. Calendar age of healthy subjects correlated positively with serum uPA and negatively with P-selectin. Age of varicose patients correlated positively with ICAM-1, VCAM-1, and ET-1. Collectively, our findings indicate that the presence of varicose veins causes a senescence-related dysfunction of vascular endothelium, which leads to the development of local and systemic proinflammatory environment.

Endothelin-1 induces cellular senescence and fibrosis in cultured myoblasts. A potential mechanism of aging-related sarcopenia

“…The senescence of myoblast has been associated with muscular dystrophy and with premature muscle wasting occurring in Bmi1 deficient young mice [ 36 ]. Senescence induced by ET-1 at vascular level has been involved in some pathologies [ 37 ], such as diabetes [ 38 ], varicosity [ 39 ] and thrombosis [ 40 ]. So, senescence induced by ET-1 at muscle level could be implicated in the development of fibrosis, exacerbating muscle damage, as the regenerative potential of skeletal muscle declines with age and this impairment is associated with an increase in tissue fibrosis [ 4 , 31 ].…”

Patients with Incompetent Valves in Chronic Venous Insufficiency Show Increased Systematic Lipid Peroxidation and Cellular Oxidative Stress Markers

“…These results showed a relationship between oxidative stress and chronic venous insufficiency at the tissue level and the systemic level beginning in the first years of the disease. Mikuła-Pietrasik et al [30] showed that the sera of varicose patients increased cell proliferation, expression of the senescence marker SA- β -Gal, and ROS production in the endothelial cells of human umbilical veins (HUVECs) compared to the sera of healthy individuals. This result suggests that the presence of oxidative stress at a systemic level is the main factor triggering the progression of the pathology.…”

“…By providing a baseline level of NO in the vein and neutralizing ROS, it makes sense that patients with low eNOS expression are more susceptible to endothelial deterioration and develop valvular incompetence (venous reflux). The low expression of eNOS may be related to CVI and any disease in which the mechanism involves endothelium dysfunction, as indicated by Mikuła-Pietrasik et al [30]. However, the expression of eNOS in the tunica adventitia suggests that it is reactive and remains functionally active.…”

TGF-β1 in Vascular Wall Pathology: Unraveling Chronic Venous Insufficiency Pathophysiology

“…Several studies concerning advanced forms of dermal pathology in CVI patients (i.e., dermal fibrosis and venous ulcers) have identified CVI dermal fibroblasts as an important target for leukocyte-derived TGF-β1, and established a link between CVI progression and increased tissue levels of TGF-β1, MMP2 activity and decreased TGF-β1 induced mitogenic responses of fibroblasts [ 4 , 15 , 120 , 129 , 130 ]. Moreover, two other studies on CVI induced dermal changes suggested a connection between TGF-β1 signaling and cellular senescence [ 130 , 131 ]. It was also proposed that a molecular mechanism in which the persistent venous hypertension (via pressure mediated mechanotransduction) could stimulate Ras production, which in turn would activate MAPK/Erks, and hence inhibit TGF-β1 regulated matrix contraction (resulting in prolonged wound healing) [ 130 ].…”