The functional role of cellular senescence during vascular calcification in chronic kidney disease

Vascular calcification (VC) has emerged as a key predictor of cardiovascular events in patients with chronic kidney disease (CKD). In recent years, an expanding body of research has put forth the concept of accelerated vascular aging among CKD patients, highlighting the significance of vascular cells senescence in the process of VC. Within the milieu of uremia, senescent vascular endothelial cells (VECs) release extracellular microvesicles (MV) that promote vascular smooth muscle cells (VSMCs) senescence, thereby triggering the subsequent osteogenic phenotypic switch and ultimately contributing to the VC process. In addition, senescent vascular progenitor or stem cells with diminished ability to differentiate into VECs and VSMCS, compromise the repair of vascular integrity, on the other hand, release a cascade of molecules associated with senescence, collectively known as the senescence-associated secretory phenotype (SASP), perpetuating the senescence phenomenon. Furthermore, SASP triggers the recruitment of monocytes and macrophages, as well as adjacent VECs and VSMCs into a pro-adhesive and pro-inflammatory senescent state. This pro-inflammatory microenvironment niche not only impacts the functionality of immune cells but also influences the differentiation of myeloid immune cells, thereby amplifying the reduced ability to effectively clear senescent cells of senescent macrophages, promoted calcification of VSMCs. The objective of this paper is to provide a comprehensive review of the contribution of vascular cell senescence to the emergence and advancement of VC. Gaining a comprehensive understanding of the involvement of cellular senescence within the vessel wall is pivotal, especially when it comes to its intersection with VC. This knowledge is essential for advancing groundbreaking anti-aging therapies, aiming to effectively mitigate cardiovascular diseases. Overview of the role of cellular senescence in regulating vascular calcification. The complex landscape of CKD hastens the senescence of vascular endothelial cells (VECs) and undermines their functional integrity, exhibiting a distinctive profile characterized by the reduced expression of nitric oxide (NO) and an elevation in reactive oxygen species (ROS). Senescent VECs release microvesicles (MVs) to trigger senescence and calcification in VSMCs. On the other hand, senescent VECs attract monocytes to the endothelium and induce the proliferation and migration of VSMCs. Pro-inflammatory phenotypic macrophages subsequently promote VSMC calcification by stimulating carbonic anhydrase I (CA1) and CA2 via secreting TNF alpha, or NLRP3 inflammasome. Mesenchymal stromal cells (MSCs) and adventitial fibroblasts (AFs) exhibit a potential for differentiation, with the ability to transform into VECs and VSMCs, contributing to the replenishment of senescent cells. However, the proliferation and differentiation capacities of senescent MSCs and AFs are diminished.