doi: 10.1161/01.CIR.0000037130.06003.11
(Circulation. 2002;106:e144.)
© 2002 American Heart Association, Inc.
Correspondence |
Further In Vivo Evidence That Cellular Senescence Is Implicated in Vascular Pathophysiology
Department of Medicine, University College London, University Street, London WC1E 6JJ, UK, E-mail j.erusalimsky@ucl.ac.uk
To the Editor:
We have read with interest the study of Minamino et al1 demonstrating endothelial cell senescence in human atherosclerotic lesions. In their study, senescence was detected using the marker known as senescence-associated ß-galactosidase (SA-ß-gal),2,3 and endothelial cells were identified by immunohistochemistry. This demonstration of the occurrence of senescent endothelial cells in vivo confirms and extends the results from the studies of Vasile et al4 and of Fenton et al,5 both of which were published in February 2001. As far as we are aware, these papers were the first to describe the occurrence of vascular cell senescence in vivo using the SA-ß-gal marker.
Vasile et al4 have demonstrated the occurrence of endothelial cells overlying human aortic atherosclerotic plaques that expressed SA-ß-gal activity and that showed differential gene expression consistent with a senescent phenotype.
Fenton et al5 used a balloon endothelial denudation model as a mechanism for promoting vascular cell replication to look for vascular cell senescence in non-atheromatous rabbit carotid arteries. Six weeks after a single denudation, SA-ß-gal–positive cells were found in both the neointima and the media, and immunohistochemical analysis identified these as endothelial and vascular smooth muscle cells. A second denudation resulted in a marked acceleration in the accumulation of senescent cells in the arterial wall. The senescent cells did not show evidence of apoptosis as assessed by terminal deoxynucleotidyltransferase-mediated dUTP nick end labelling analysis.
The evidence that endothelial cell senescence can occur in vivo seems to be growing, and it is encouraging to see another paper that supports this contention.
References
1. Minamino T, Miyauchi H, Yoshida T, et al. Endothelial cell senescence in human atherosclerosis: role of telomere in endothelial dysfunction. Circulation. 2002; 105: 1541–1544.
2. Dimri GP, Lee X, Basile G, et al. A biomarker that identifies senescent human cells in culture and in aging skin in vivo. Proc Natl Acad Sci U S A. 1995; 92: 9363–9367.
3. Kurz DJ, Decary S, Hong Y, et al. Senescence-associated ß-galactosidase reflects an increase in lysosomal mass during replicative ageing of human endothelial cells. J Cell Science. 2000; 113: 3613–3622.[Abstract]
4. Vasile E, Tomita Y, Brown LF, et al. Differential expression of thymosin ß-10 by early passage and senescent vascular endothelium is modulated by VPF/VEGF: evidence for senescent endothelial cells in vivo at sites of atherosclerosis. FASEB J. 2001; 15: 458–466.
5. Fenton M, Barker S, Kurz DJ, et al. Cellular senescence after single and repeated balloon catheter denudations of rabbit carotid arteries. Arterioscler Thromb Vasc Biol. 2001; 21: 220–226.
Response
Department of Cardiovascular Science and Medicine, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba, Japan
Department of Pathology, Teikyo University Ichihara Hospital, Ichihara, Chiba, Japan
The Third Department of Internal Medicine, Teikyo University Ichihara Hospital, Ichihara, Chiba, Japan
We thank Drs Erusalimsky and Fenton for their interest in our article.1 As Drs Erusalimsky and Fenton pointed out, Vasile et al2 reported that senescence-associated ß-galactosidase (ß-gal) activity was detected in human aorta obtained from older patients. They identified these ß-gal–positive cells as endothelial cells with an immunostaining. However, they did not perform immunostainings for other vascular cell markers, such as 
-smooth muscle actin for vascular smooth muscle cells and CD68 for macrophages to evaluate atherosclerotic lesions. More importantly, they did not examine ß-gal activity in normal lesions and consequently failed to show the association between endothelial cell senescence and atherosclerosis. In contrast, we identified atherosclerotic lesions using immunostainings for three vascular cell markers and showed that ß-gal positive cells were observed in human atherosclerotic plaques of the coronary arteries but not in non-atherosclerotic lesions of the internal mammary arteries from the same patients who had ischemic heart disease. Thus, our data clearly indicate the relationship between cellular senescence and atherosclerosis. Moreover, we detected senescent vascular smooth muscle cells in human advanced atherosclerotic plaques by a double staining for -smooth muscle actin and ß-gal activity that had not been demonstrated previously. Our findings are consistent with the observations by Fenton et al3 who reported the occurrence of senescent vascular cells in rabbit carotid arteries after injury. However, this artificial animal model does not reflect the clinical settings — in particular, human atherogenesis. Therefore, their data also failed to demonstrate the possible role of vascular cell senescence in the pathogenesis of human atherosclerosis.
We have previously shown an important role of telomere and telomerase in vascular cell senescence in vitro.4,5 Progressive telomere shortening in vivo has been observed in the regions susceptible to atherosclerosis.6 Indeed, in this article,1 we provide direct evidence indicating an importance of telomere in endothelial dysfunction in vitro and likely in vivo.
Combined, our data suggest a critical role of vascular cell senescence in the pathogenesis of human atherosclerosis and provide new insights into vascular biology.
References
1. Minamino T, Miyauchi H, Yoshida T, et al. Endothelial cell senescence in human atherosclerosis: role of telomere in endothelial dysfunction. Circulation. 2002; 105: 1541–1544.
2. Vasile E, Tomita Y, Brown LF, et al. Differential expression of thymosin beta-10 by early passage and senescent vascular endothelium is modulated by VPF/VEGF: evidence for senescent endothelial cells in vivo at sites of atherosclerosis. FASEB J. 2001; 15: 458–466.
3. Fenton M, Barker S, Kurz DJ, et al. Cellular senescence after single and repeated balloon catheter denudations of rabbit carotid arteries. Arterioscler Thromb Vasc Biol. 2001; 21: 220–226.
4. Minamino T, Kourembanas S. Mechanisms of telomerase induction during vascular smooth muscle cell proliferation. Circ Res. 2001; 89: 237–243.
5. Minamino T, Mitsialis SA, Kourembanas S. Hypoxia extends the life span of vascular smooth muscle cells through telomerase activation. Mol Cell Biol. 2001; 21: 3336–3342.
6. Chang E, Harley CB. Telomere length and replicative aging in human vascular tissues. Proc Natl Acad Sci U S A. 1995; 92: 11190–11194.
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