br Transparency document br Introduction Aging as a
Introduction Aging, as a global health concern, is a challenge to individual health and public health policy. In the aging process, tissue and organ functions are progressively lost, at least in part, thereby leading to a high risk of age-related diseases and an increased risk of mortality . Specifically, cerebra-cardiovascular diseases are the leading cause of mortality among all age-related diseases and are responsible for more than half of all deaths in developed countries, such as Europe [2,3]. One characteristic of aging is the accumulation of senescent cells, which is the result of an imbalance between damage to cells and an insufficient clearance or repair of damaged cells in aged organisms . Quantitative data have indicated that in lungs or livers, senescent cells in aged mice were approximately twice the percentage of those in young mice , and the accumulation of senescent cells in arterial walls has also been reported by numerous researchers . With emerging data, cellular senescence, which has primarily been defined as cellular growth arrest or withdrawal from the cell cycle, has been implicated as an important contributor to age-related diseases . Vascular smooth muscle cells (VSMCs), as basic ingredients of the vascular wall and the sole cell type in the arterial medial layer, play critical roles in vascular physiological functions. VSMCs and the extracellular matrix (ECM) synthesized by VSMCs are the major regulators of the contractile tone of arteries, thus contributing to the maintenance of arterial peripheral resistance, the regulation of blood pressure, the distribution and redistribution of blood flow, and the repair of arteries . Changes in VSMCs and ECM, particularly in large arteries, such as the Cell Counting Kit-8 (CCK-8) and the carotid, would influence arterial compliance. Increased arterial stiffness suggests an impaired transformational function of arteries, in which blood flow cannot be changed from pulsatile to steady . Moreover, VSMCs are not only the regulator but also the effector in arteries. VSMCs were able to respond to many circulating vasoactive substances and act as a sensor of mechanical forces and transduce them into various biochemical signals . VSMCs are the focus of substantial attention in vascular studies because of their importance in vascular structure and function.
VSMC senescence: what is it? Cellular senescence was first introduced by Hayflick and Moorhead  to describe the concept that cells can no longer divide (also referred to as the Hayflick limit). Campisi J and his colleagues  summarized four common characteristics of senescent cells: 1) growth arrest, 2) apoptosis resistance, 3) altered gene expression, and 4) changes in senescent markers. With the deeper knowledge of cellular senescence, senescence is currently beyond the initial growth arrest, representing complex cellular states in which both phenotypical and mechanistic changes are involved, and the relationships between cellular senescence and age-related diseases are generally identified . VSMC senescence conforms to the common characteristics of senescent cells. Similar to other senescent cells, senescent VSMCs have a low ability of mitotic division  and changes in cell signaling pathways and senescent markers, for example, the senescence-associated beta-galactosidase (SA-β Gal) activity and the levels of p16, p38, p53-p21, and phospho-histone H2A.X . Apart from these changes, there are special characteristics of VSMC senescence, including changes in the responsiveness of VSMCs to contracting and relaxing mediators, changes in VSMC phenotypes from contractile to synthetic during the senescent process, changes in specific signaling pathways in VSMCs, such as protein kinase G-1 (PKG-1) and voltage-dependent and Ca2+-activated K+ (BKCa) channels, and changes in the communications between VSMCs and the ECM . Senescent VSMCs could directly influence the arterial tone with these special characteristics.