Molecular Mechanisms of Vascular Calcification

Abstract

Abstract-Vascular calcification increasingly afflicts our aging and dysmetabolic population. Once considered a passive process, it has emerged as an actively regulated form of calcified tissue metabolism, resembling the mineralization of endochondral and membranous bone. Executive cell types familiar to bone biologists, osteoblasts, chondrocytes, and osteoclasts, are seen in calcifying macrovascular specimens. Lipidaceous matrix vesicles, with biochemical and ultrastructural "signatures" of skeletal matrix vesicles, nucleate vascular mineralization in diabetes, dyslipidemia, and uremia. Skeletal morphogens (bone morphogenetic protein-2 (BMP) and BMP4 and Wnts) divert aortic mesoangioblasts, mural pericytes (calcifying vascular cells), or valve myofibroblasts to osteogenic fates. Paracrine signals provided by these molecules mimic the epithelialmesenchymal interactions that induce skeletal development. Vascular expression of pro-osteogenic morphogens is entrained to physiological stimuli that promote calcification. Inflammation, shear, oxidative stress, hyperphosphatemia, and elastinolysis provide stimuli that: (1) promote vascular BMP2/4 signaling and matrix remodeling; and (2) compromise vascular defenses that limit calcium deposition, inhibit osteo/chondrogenic trans-differentiation, and enhance matrix vesicle clearance. In this review, we discuss the biology of vascular calcification. We highlight how aortic fibrofatty tissue expansion (adventitia, valve interstitium), the adventitial-medial vasa, vascular matrix, and matrix vesicle metabolism contribute to the regulation of aortic calcium deposition, with greatest emphasis placed on diabetic vascular disease. Key Words: diabetes Ⅲ vascular calcification Ⅲ Wnt signaling Ⅲ bone morphogenetic proteins Ⅲ oxylipids W ith advanced age, vascular inflammation, hypertension, and certain metabolic disorders, calcium accumulates in the arterial macrovasculature. 1 Calcification of aortic valve leaflets and atherosclerotic plaques have long been recognized as clinically important. 2 However, medial artery calcification (MAC) also portends mortality and amputation risk. 1,[3][4][5] Studies of vascular calcified tissue metabolism significantly lag behind those of skeletal metabolism. Executive cell types familiar to bone biologists are seen in calcifying aortic specimens. 1,6 As in bone, endothelial, mesenchymal, and hematopoietic cell lineages control vascular mineral accumulation, with cellular activities entrained to morphogenetic, metabolic, inflammatory, and mechanical demands placed on each vascular segment. 1 We provide a brief overview of vascular calcification, emphasizing how paracrine osteogenic signals recruited by dysmetabolic insults promote aortic calcium deposition in diabetic vascular disease. We point to emerging evidence that inflammation, mechanical, and metabolic oxidative stresses not only provide stimuli that induce vascular osteogenic morphogens but also compromise defense mechanisms that limit vascular calcium deposition. 1 Aortic MACMAC is a high...

Atherosclerotic Calcification: Wnt Is the Hint

“…There are 4 histoanatomic variants of VC, which include medial artery calcification, atherosclerotic intimal calcification, cardiac valve calcification, and soft tissue calciphylaxis or calcific uremic arteriolopathy 38, 47. A major breakthrough in the study of VC was the realization that the ectopic deposition of calcium in vascular structures is similar to intramembranous and endochondral ossification in bone development 48. As early as the 19th century, bonelike tissue was identified within atherosclerotic arteries 49…”

“…Advanced calcific lesions can develop woven bone and even commence hematopoiesis. This remodeling of the vasculature can extend to the point of acquiring some functional characteristics of bone, offering the perspective that VC occurs in a manner similar to bone development 48, 60, 61, 62. Briefly, osteogenesis involves formation of mesenchymal cell condensations, which differentiate into bone‐forming cells for intramembranous or endochondral ossification 63, 64.…”

Role of extracellular membrane vesicles in the pathogenesis of various diseases, including cancer, renal diseases, atherosclerosis, and arthritis

“…In Trousseau's syndrome, widespread thromboembolism becomes the dominant feature of the patient's cancer-related illness, and often serves as the cause of death. 68 Osteoarthritis Osteoarthritis (OA) is a progressive disease of unknown etiology characterized by degeneration of articular cartilage, particularly in large, weight-bearing joints (namely the knee Bobryshev et al, 18 Chen et al, 15 Demer and Tintut, 22 Giachelli, 21 Hsu and Camacho, 4 Kim, 19 Li et al, 20 Reynolds et al, 17 Shao et al, 23 Tanimura Amabile et al, 29 Bakouboula et al, 27 Chironi et al, 28 Dvorak, 30 Enjeti et al, 33 Satta et al 32 …”

Pathologic calcification of adult vascular smooth muscle cells differs on their crest or mesodermal embryonic origin

“…(5) In patients with chronic kidney disease (CKD), depending on the pathologic stage, associated hyperphosphatemia leads to calcification of large arteries, including aortic arch and/or abdominal aorta. (6)(7)(8) Compared with the tremendous progress made during the past two decades in elucidating the common molecular mechanisms underpinning the formation of vascular calcifications, (1,3) little is known about the determinants that would influence a specific vessel to be affected and another to be relatively protected in response to a particular calcifying risk factor. We hypothesized that the range of prevalence of calcification in the different arteries could be explained by the fact that vessels are not created equal.…”