Contributions of the Endothelium to Vascular Calcification

Abstract

Vascular calcification (VC) increases morbidity and mortality and constitutes a significant obstacle during percutaneous interventions and surgeries. On a cellular and molecular level, VC is a highly regulated process that involves abnormal cell transitions and osteogenic differentiation, re-purposing of signaling pathways normally used in bone, and even formation of osteoclast-like cells. Endothelial cells have been shown to contribute to VC through a variety of means. This includes direct contributions of osteoprogenitor cells generated through endothelial-mesenchymal transitions in activated endothelium, with subsequent migration into the vessel wall. The endothelium also secretes pro-osteogenic growth factors, such as bone morphogenetic proteins, inflammatory mediators and cytokines in conditions like hyperlipidemia, diabetes, and renal failure. High phosphate levels caused by renal disease have deleterious effects on the endothelium, and induction of tissue non-specific alkaline phosphatase adds to the calcific process. Furthermore, endothelial activation promotes proteolytic destruction of the internal elastic lamina that serves, among other things, as a stabilizer of the endothelium. Appropriate bone mineralization is highly dependent on active angiogenesis, but it is unclear whether the same relationship exists in VC. Through its location facing the vascular lumen, the endothelium is the first to encounter circulating factor and bone marrow-derived cells that might contribute to osteoclast-like versus osteoblast-like cells in the vascular wall. In the same way, the endothelium may be the easiest target to reach with treatments aimed at limiting calcification. This review provides a brief summary of the contributions of the endothelium to VC as we currently know them.

The Role of Sirtuins in Osteogenic Differentiation of Vascular Smooth Muscle Cells and Vascular Calcification

“…Normally, a monolayer of endothelial cells forms the innermost layer that acts as a barrier between the vessel lumen and the vessel wall in order to maintain the non-thrombotic surface and quiescence in the vascular wall. Under pathological conditions, endothelial cells also respond to different stimuli and exist in various activation states, including inflammatory, angiogenic, and osteogenic phenotypes ( 25 – 27 ). Growing evidence suggests that endothelial cells influence the development of VC in a variety of pathways, including transition to mesenchymal and osteoblastic lineages, secretion of calcific growth factors, disruption of the proteolytic activity of IELs, induction of endothelial alkaline phosphatase and inappropriate interactions with underlying cells ( 27 ).…”

MicroRNA-34a: the bad guy in age-related vascular diseases

“…VC shares some common features with bone morphogenesis and recent studies have highlighted VC as an actively cell-mediated process driven primarily by VSMCs reprogramming towards an osteochondrogenic lineage [ 125 , 126 ]. Likewise, stressed ECs can undergo osteogenic transformation through endothelial–mesenchymal transition [ 127 ]. Aging and several other risk factors, like hyperglycemia, hyperlipidemia, dysregulated mineral metabolism (hyperphosphatemia and intermittent hypercalcemia), along with uremic toxins and oxidative stress promote VSMCs shift from a contractile to synthetic phenotype that lose the ability to produce endogenous calcification inhibitors, namely, Osteopontin, Matrix Gla protein and pyrophosphate (PPi).…”

Anti-Inflammatory Effects of Thymoquinone in Atherosclerosis: A Mini Review

“…Various pathological events are involved in vascular remodeling in response to vascular damage, including endothelial dysfunction, vascular smooth muscle cell (VSMC) proliferation and migration, arterial calcification, and extracellular matrix remodeling ( Wang and Khalid, 2018 ; Zhang et al, 2021 ). Such injury-induced vascular remodeling is primarily due to excessive proliferation and migration of VSMCs and medial VSMC invasion into the intimal space, eventually leading to neointimal formation.…”