A paper by Japanese researchers has recently been published (click here) demonstrating the importance of vascular smooth muscle cell (VSMC) senescence in calcification. Vascular calcification is important because it can lead to reduced elasticity and compliance of arteries and is also a prominent feature of advanced atherosclerotic plaques. Although the process of calcification appears to be similar to that of bone formation (Abedin et al, 2004), little is known about the underlying mechanism. Nakano-Kurimoto et al have confirmed some of the findings published earlier by Burton et al (click here), but have taken it many steps forward with their in-depth investigation.
As well as providing further evidence for a role of VSMC senescence in calcification, these studies also demonstrate the importance of understanding the senescent specific changes which may occur in cells associated with age-related disease/dysfunction. Such an understanding may not only provide answers regarding mechanisms of disease development, but may also provide biomarkers of tissue specific ageing.
Replicative senescence of vascular smooth muscle cells
enhances the calcification through initiating the osteoblastic
transition
Nakano-Kurimoto R, Ikeda K, Uraoka M, Nakagawa Y, Yutaka K, Koide M, Takahashi T, Matoba S, Yamada H,Okigaki M, Matsubara H
Medial artery calcification, which does not accompany lipid or cholesterol deposit, preferentially occurs in elderly population, but its underlying mechanisms remain unclear. Here, we investigated the potential role of senescent vascular smooth muscle cells (VSMCs) in the formation of senescence-associated medial calcification. Replicative senescence was induced by the extended passages (until passage 11-13) in human primary VSMCs, and cells in early passage (passage 6) were used as control young cells. VSMC calcification was markedly enhanced in the senescent cells comparing with that in the control young cells. We identified that genes highly expressed in osteoblasts, such as alkaline phosphatase (ALP) and type-I collagen, were significantly up-regulated in the senescent VSMCs, suggesting their osteoblastic transition during the senescence. Knockdown of either ALP or type-I collagen significantly reduced the calcification in the senescent VSMCs. Of note, runt-related transcription factor-2 (RUNX-2), a core transcriptional factor that initiates the osteobalstic differentiation, was also up-regulated in the senescent VSMCs. Knockdown of RUNX-2 significantly reduced the ALP expression and calcification in the senescent VSMCs, suggesting that RUNX-2 is involved in the senescence-mediated osteoblastic transition. Furthermore, immunohistochemistry of aorta from klotho-/- aging model mouse demonstrated in vivo emergence of osteoblast-like cells expressing RUNX-2 exclusively in the calcified media. We also found that statin and Rho-kinase inhibitor effectively reduced the VSMC calcification by inhibiting Pi-induced apoptosis and potentially enhancing matrix Gla protein expression in the senescent VSMCs. These findings strongly suggest an important role of senescent VSMCs in the pathophysiology of senescence-associated medial calcification, and the inhibition of osteoblastic transition could be a new therapeutic approach for the prevention of senescence-associated medial calcification. Key words: vascular calcification, medial calcification, senescence, RUNX-2.
