Senescent cells accumulate throughout the body with age. They are created constantly due to stresses placed upon cells, and when somatic cells reach the Hayflick limit on replication, and are cleared by the immune system. This process of clearance slows down with age, unfortunately, and so a burden of lingering senescent cells begins to build up. Senescent cells are disruptive to tissue structure and function, even when present in comparatively small numbers relative to other cells in a tissue, as a result of the pro-growth, pro-inflammatory signals that they generate.
Atherosclerosis involves the generation of fatty lesions that narrow and weaken blood vessels, and is the leading cause of human mortality, as rupture of these lesions causes stroke and heart attack. We might view it as a condition of macrophage dysfunction, as these are the cells tasked with cleaning up the excess cholesterol and cell debris that form the bulk of an atherosclerotic lesion. The lesions grow to the degree that macrophages become overwhelmed and begin to die, calling for more support as they do so. In this context, to what degree is atherosclerosis driven by cellular senescence? And which sort of senescent cells?
It is known that cells become senescent in and around atherosclerotic lesions, and that clearing them in animal models helps to slow progression of pathology; one can speculate on the mechanisms by which various types of senescent cell can contribute to make the lesion environment worse. Sadly, no-one has yet run clinical trials of the known senolytic drugs capable of clearing senescent cells in human patients. Nor are they likely too, given the high costs of such a trial, and the inability to profit from new data on existing drugs.
Atherosclerosis is a chronic cardiovascular disease (CVD) that poses significant risks to human health, and is the underlying cause of peripheral vascular disease, coronary heart disease, and stroke. The pathogenesis of atherosclerosis is complex and involves various cell types, including endothelial cells (ECs), vascular smooth muscle cells (SMCs), adventitial fibroblasts, macrophages, and other immune cells. Key factors in the development of atherosclerosis include endothelial dysfunction, leukocyte adhesion, foam macrophage formation, and SMC phenotypic transition.
Endothelial dysfunction is considered the initial step in atherosclerosis, and in its broadest sense, it encompasses a constellation of nonadaptive alterations in functional phenotype, which have important implications for the regulation of hemostasis and thrombosis, local vascular tone, redox balance, and the orchestration of acute and chronic inflammatory reactions within the arterial wall. ECs that line elastic arteries, such as the aorta, carotid artery, and femoral artery, have critical functions in maintaining vascular homeostasis. The primary function of the endothelium is to produce nitric oxide (NO) and other vasoactive substances to regulate vascular tone.
ECs form a continuous monolayer barrier that controls substance exchange among the lumen, vascular wall, and parenchyma. A specialized barrier function of the endothelium involves its immunoregulatory effects on leukocyte recruitment. Quiescent endothelium is immunosuppressive, with a surface glycoprotein profile that prevents leukocyte adhesion, crawling, and extravasation. Upon tissue injury and inflammatory stress, activated ECs present adhesive molecules, such as vascular cell adhesion molecule-1 (VCAM-1), to the cell surface to facilitate the transendothelial migration of leukocytes. The reactive, pro-inflammatory phenotype of ECs is indispensable for tissue repair after acute injury. However, in the context of chronic tissue damage, such as atherosclerosis, persistent endothelial inflammation becomes pathogenic. Moreover, the regenerative capacity of ECs is intrinsically critical to the re-endothelialization of the surface-eroded arterial lumen and the stabilization of atherosclerotic lesions. Notably, most of these endothelial dysfunctions are associated with endothelial cell senescence and death.
Cellular senescence is a process in which cells undergo permanent cell cycle arrest, with an altered secretome to remodel neighboring cells and the extracellular matrix (ECM) microenvironment. Notably, vascular aging in animal models and humans is characterized by impaired endothelium-dependent dilation (EDD), perturbed fibrinolysis, enhanced permeability, and aberrant angiogenesis. In humans, endothelium-dependent vasodilation, usually measured as flow-mediated dilation of the radial artery, serves as a non-invasive marker of vascular aging and cardiovascular damage, even in the absence of clinical symptoms. Importantly, cellular senescence of the endothelium is an integral component of vascular aging, as well as atherosclerosis. EC senescence triggers structural and functional deterioration of the vascular wall by not only deterring re-endothelialization and barrier reconstitution at the injury zone, but also promoting an inflammatory and thrombotic niche via the senescence secretome, thereby contributing to the development and progression of CVD.