Arterial Stiffness: A Focus on Vascular Calcification and Its Link to Bone Mineralization

Abstract

This review focuses on the association between vascular calcification and arterial stiffness, highlighting the important genetic factors, systemic and local microenvironmental signals, and underlying signaling pathways and molecular regulators of vascular calcification. Elevated oxidative stress appears to be a common procalcification factor that induces osteogenic differentiation and calcification of vascular cells in a variety of disease conditions such as atherosclerosis, diabetes mellitus, and chronic kidney disease. Thus, the role of oxidative stress and oxidative stress-regulated signals in vascular smooth muscle cells and their contributions to vascular calcification are highlighted. In relation to diabetes mellitus, the regulation of both hyperglycemia and increased protein glycosylation, by AGEs (advanced glycation end products) and O-linked β-N-acetylglucosamine modification, and its role in enhancing intracellular pathophysiological signaling that promotes osteogenic differentiation and calcification of vascular smooth muscle cells are discussed. In the context of chronic kidney disease, this review details the role of calcium and phosphate homeostasis, parathyroid hormone, and specific calcification inhibitors in regulating vascular calcification. In addition, the impact of the systemic and microenvironmental factors on respective intrinsic signaling pathways that promote osteogenic differentiation and calcification of vascular smooth muscle cells and osteoblasts are compared and contrasted, aiming to dissect the commonalities and distinctions that underlie the paradoxical vascular-bone mineralization disorders in aging and diseases.

Keywords: arterial stiffness; atherosclerosis; diabetes mellitus; renal insufficiency, chronic; vascular calcification.

Figure 1.

Vascular calcification resembles the process of osteoblast differentiation and mineralization, involving osteogenic differentiation, matrix maturation and mineralization. Systemic and local microenvironmental conditions associated with atherosclerosis, diabetes mellitus, CKD and aging induce osteogenic differentiation of vascular cells and promote matrix remodeling and mineralization, leading to vascular calcification.

Figure 2.

Genetic and cellular determinants that regulate pyrophosphate and phosphate homeostasis and the formation of hydroxyapatite crystals in the ECM. The key enzymes (ENPP1, CD73 and ALP) and transporters (ANK and ABCC6) that mediate the ATP metabolic pathway and pyrophosphate catalysis are detailed. The functions of matrix vesicle (MV) that carry and transport calcium/phosphate (Ca⁺⁺/P_i) and matrix proteins to ECM for the formation of hydroxyapatite crystals and the secretion factors that are important for calcium binding and inhibition of the formation of hydroxyapatite crystals (MGP, OPN and Fetuin-A) are highlighted.

Figure 3.. Differential responses to pathogenic inducers in vasculature and bone environment leads to opposite outcomes in mineralization of bone and vascular cells.

Aging and pathogenic conditions including atherosclerosis, diabetes and CKD are associated with systemic and tissue microenvironmental changes, such as increased oxidative stress, hyperglycemia, and impaired Ca⁺⁺/P_i homeostasis. The difference in basal levels of TNAP, high in bone and low in VSMC, and their different responses to the pathologic conditions activate various intrinsic signaling cascades that eventually lead to opposite effects on the key osteogenic transcription factor Runx2, upregulating Runx2 in VSMC that promotes vascular calcification whereas inhibiting Runx2 in osteoblasts that decrease bone mineralization.