Senescent Microvesicles: A Novel Advance in Molecular Mechanisms of Atherosclerotic Calcification

Abstract

Atherosclerosis, a chronic inflammatory disease that causes the most heart attacks and strokes in humans, is the leading cause of death in the developing world; its principal clinical manifestation is coronary artery disease. The development of atherosclerosis is attributed to the aging process itself (biological aging) and is also associated with the development of chronic diseases (premature aging). Both aging processes produce an increase in risk factors such as oxidative stress, endothelial dysfunction and proinflammatory cytokines (oxi-inflamm-aging) that might generate endothelial senescence associated with damage in the vascular system. Cellular senescence increases microvesicle release as carriers of molecular information, which contributes to the development and calcification of atherosclerotic plaque, as a final step in advanced atherosclerotic plaque formation. Consequently, this review aims to summarize the information gleaned to date from studies investigating how the senescent extracellular vesicles, by delivering biological signalling, contribute to atherosclerotic calcification.

Hypoxia-Inducible Factor-1α: The Master Regulator of Endothelial Cell Senescence in Vascular Aging

“…This theory proposes that an imbalance between the demand for and supply of O 2 in the arterial wall is a critical factor in the development of atherosclerosis [105]. As a consequence, macrophages become apoptotic, a necrotic core is built, and there is an eventual increase in angiogenesis, linking senescent cells to atherosclerosis progression [7]. Therefore, the anoxemia theory is postulated to explain the progress of atheroma plaque.…”

“…In vascular aging, the arterial vascular wall is affected by an increase in both senescent endothelial cells (ECs) as well as vascular smooth muscle cells (VSMCs) [5]. The exact mechanism that mediates ECs to become senescent in the vascular wall is still not fully understood; however, much evidence has revealed a crucial role for hypoxia-inducible factor-1α (HIF-1α) in the development of the senescent phenotype and the progression of atherosclerosis [6][7][8][9][10].…”

“…SASP occurs regardless of the stimulus that initiates senescence, such as a replicative senescence model in vitro, aging in vivo, and even when senescent cells appear as a consequence of stressful stimuli, known as stress-induced premature senescence (SIPS) [14]. SIPS is considered a reversible phenomenon [7]. In any case, the secretory phenotype includes the secretion of cytokines, growth factors, proteases, and extracellular vesicles (EVs), which exert a paracrine function affecting neighboring cells and propagate the senescent phenotype [15].…”

“…This new concept, based on the studies of molecular mechanisms in the evolution of cellular senescence to avoid age-associated diseases, offers a new approach to secure the survival of senescent cells [1]. For this purpose, senotherapy (or senolysis) has been coined for therapies where senolytic drugs, which are intended to eliminate senescent cells by apoptosis [1,7,8,17,18], have shown beneficial effects in experimental models and human clinical trials [19][20][21][22][23]. Senolytic drugs may be useful as inhibitors of the progression of aging per se or disorders associated with premature aging, such as CVD [18,24,25].…”

Indoxil sulfato induce senescencia y liberación de microvesículas en células endoteliales que promueven la calcificación vascular

“…En concreto, aquellas producidas por células endoteliales se pueden cuantificar en sangre periférica y usarse como posible biomarcador para evaluar el daño endotelial [3,11,12]. De este modo, su caracterización fenotípica podría proporcionar información sobre el mecanismo por el cual las células endoteliales causan lesiones vasculares y, por tanto, median el desarrollo de las enfermedades cardiovasculares (ECV) [13,14].…”