Abstract
Whereas a healthy endothelium maintains physiological vascular functions, endothelial damage contributes to the development of cardiovascular diseases. Endothelial senescence is the main determinant of endothelial dysfunction and thus of age-related cardiovascular disease. The objective of this study is to test the involvement of microRNA-126 and HIF-1α in a model of replicative endothelial senescence and the interrelationship between both molecules in this in vitro model. We demonstrated that senescent endothelial cells experience impaired tube formation and delayed wound healing. Senescent endothelial cells failed to express HIF-1α, and the microvesicles released by these cells failed to carry HIF-1α. Of note, HIF-1α protein levels were restored in HIF-1α stabilizer-treated senescent endothelial cells. Finally, we show that microRNA-126 was downregulated in senescent endothelial cells and microvesicles. With regard to the interplay between microRNA-126 and HIF-1α, transfection with a microRNA-126 inhibitor downregulated HIF-1α expression in early passage endothelial cells. Moreover, while HIF-1α inhibition reduced tube formation and wound healing closure, microRNA-126 levels remained unchanged. These data indicate that HIF-1α is a target of miRNA-126 in protective and reparative functions, and suggest that their therapeutic modulation could benefit age-related vascular disease.
Highlights
The vascular endothelium, the epithelial layer that lines the inner surface of blood and lymphatic vessels, forms a nearly 1-kg organ and consists of approximately 1–6 × 1013 cells
Senescence was measured using the fluorogenic substrate C12FDG, which is cleaved by β-galactosidase, generating a fluorescent product that is well retained by the cells
Cell senescence is defined as a type of status characterized by the irreversible arrest of cell proliferation and is considered the main contributor to aging and aging-related disease[30]
Summary
The vascular endothelium, the epithelial layer that lines the inner surface of blood and lymphatic vessels, forms a nearly 1-kg organ and consists of approximately 1–6 × 1013 cells. Endothelial cells have important physiological functions, and their dysfunction can contribute to several pathological conditions, including cardiovascular disease. Angiogenesis consists of the sprouting of new capillaries from existing vessels to form functional vascular networks in wound healing and response to tissue ischemia (e.g., peripheral artery disease and chronic angina) and contributes to pathological processes (e.g., cancer, atherosclerosis) when this response is inappropriate[4,5]. Passage endothelial cells n = 3 pools; senescent endothelial cells. The regulation of blood vessel formation is fundamental to many physiological and pathological processes, and angiogenesis is a major area with regard to developing novel therapeutic approaches for diseases, from ischemia to cancer[9]. Endothelial senescence (ES) has been associated with the initiation or progression of cardiovascular diseases (CVD). Several experimental models, such as the Hayflick replicative senescence model[17], have been useful in identifying the cellular and molecular changes that occur during cellular senescence and aging
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