Review
This Review is part of a thematic series on Pathobiology of Calcific Vasculopathy and Valvulopathy, which includes
the following articles:
Thematic Series on the Pathobiology of Vascular Calcification: An Introduction
Molecular Imaging Insights into Early Inflammatory Stages of Arterial and Aortic Valve Calcification
Calcific Aortic Valve Stenosis: Methods, Models, and Mechanisms
Fetuin Regulation of Calcified Matrix Metabolism
Matricrine Cues and Substrate Compliance in the Pathobiology of Calcific Valvular Disease
Oxylipids and RANKL Signaling in Macrovascular Calcification
Osteogenic BMP-Wnt Signaling in Valvular and Vascular Sclerosis
Calcium-Phosphate Homeostasis in the Arterial Calcification of CKD
Downloaded from http://circres.ahajournals.org/ by guest on June 18, 2017
Molecular Genetics of Calcific Vasculopathy
Dwight A. Towler, Guest Editor
Thematic Series on the Pathobiology of
Vascular Calcification
An Introduction
Dwight A. Towler, Linda L. Demer
Abstract: Vascular calcification increasingly afflicts our aging, dysmetabolic population. Once considered only a
passive process of dead and dying cells, data from multiple laboratories worldwide have converged to
demonstrate that vascular calcification is a highly regulated form of biomineralization. The goal of this thematic
review series is to highlight what is known concerning the biological “players” and “game rules” with respect to
vascular mineral metabolism. Armed with this understanding, it is hoped that novel therapeutic strategies can
be crafted to prevent and treat vascular calcium accrual, to the benefit of our patients afflicted with
arteriosclerotic valvular and vascular diseases. (Circ Res. 2011;108:1378-1380.)
Key Words: arteriosclerosis 䡲 atherosclerosis 䡲 vascular calcification 䡲 calcific aortic stenosis 䡲 review
I
elderly; however, its prevalence actually corresponds roughly
with age, with coronary calcification occurring in ⬇20% of
young adults, ⬇60% of those in middle age, and ⬇90% of the
elderly.2– 4 Moreover, coronary calcification is now widely
used as the preferred marker for the earliest “subclinical”
phase of atherosclerosis.5 Additionally, implementation of
tibial artery calcification scoring portends lower-extremity
amputation risk, outperforming traditional methods of
n a recent meta-analysis from New Zealand,1 Bolland and
colleagues reported that dietary calcium supplementation is
associated with a significant increase in risk for myocardial
infarction. Although the mechanism of this association is
unknown, the finding calls attention to the process of artery
wall calcification. For decades, calcific modification of the
cardiovascular system was considered an uncommon condition limited to the most advanced atherosclerosis in the
Original received February 18, 2011; revision received February 26, 2011; accepted March 4, 2011. In March 2011, the average time from submission
to first decision for all original research papers submitted to Circulation Research was 13.2 days.
From the Department of Medicine, Division of Endocrinology (D.A.T.), Washington University in St Louis, St Louis, MO; and Department of
Medicine, Division of Cardiology (L.L.D.), David Geffen School of Medicine at UCLA, Los Angeles, CA.
Correspondence to Dwight A. Towler, MD, PhD, Department of Medicine, Division of Endocrinology, Washington University in St Louis, 660 S
Euclid Ave, St Louis, MO 63110 (E-mail [email protected]); or Linda L. Demer, MD, PhD, Department of Medicine, Division of Cardiology, David
Geffen School of Medicine at UCLA, 10833 LeConte Ave, Los Angeles, CA 90095 (E-mail [email protected]).
© 2011 American Heart Association, Inc.
Circulation Research is available at http://circres.ahajournals.org
DOI: 10.1161/CIRCRESAHA.110.234419
1378
Towler and Demer
Downloaded from http://circres.ahajournals.org/ by guest on June 18, 2017
evaluation such as ankle-brachial indices.6 Clearly, the
burgeoning unmet clinical needs in cardiovascular medicine will require a better understanding of the molecular
mechanisms that control the initiation and progression of
vascular mineralization.
Consistent with this need, our understanding of how
arterial tissues undergo this mineralizing transformation has
grown rapidly, as reflected in the surge of publications
identified by a search of PubMed for the key phrase “vascular
calcification.” There was only 1 such publication in 1994; 6
in 1995; about 12 per year from 1996 to 1999; 15 in 2000;
about 75 per year from 2001 to 2004; and about 150 per year
from 2005 to 2009. The number shot to 280 in 2010, and in
the first 19 days of January 2011, there were as many
publications using this term as there were in all of 1995 and
1996 combined.
Calcium deposits in the artery wall often contain fully
formed bone tissue (ie, true ossification), including trabeculae, osteoblasts, osteoclasts, woven bone, and even marrow.7,8
However, even in the absence of overt vascular ossification,
the molecular “fingerprints” of active osteochondrogenic
gene regulatory programs are present in virtually all types of
vascular calcification. At the molecular level, the regulatory
factors that drive cardiovascular mineralization overlap with
those driving embryonic osteogenesis and postnatal skeletal
repair. Key factors include potent morphogens that activate
osteogenic bone morphogenetic protein and Wnt
(wingless-type MMTV integration site family member)
signaling cascades. The investigators who have elucidated
these mechanisms—Kristina Bostrom, Nalini Rajamannan,
and Dwight Towler—will review these underlying osteogenic mechanisms.
Calcific vasculopathy was not limited only to modern
humans and our 21st century lifestyle. Aortic wall calcification was detected by computed tomographic scan of a natural
mummy found in ice floes of the Alps; the remains were
estimated to be from 5300 years ago. In the present series,
Robert Terkeltaub and Frank Rutsch (colleagues who identified the gene defect responsible for the previously mysterious
disorder, generalized arterial calcification of infancy) will
review the molecular genetics that predispose or protect
humankind from vascular calcification.
The most severe calcific vasculopathy occurs in patients
with chronic kidney disease, particularly those requiring
dialysis, in whom the metabolic milieu generates a “perfect
storm” in vascular calcification. This has been linked to
abnormalities of phosphate metabolism, discovered by Cecilia Giachelli, as well as calcium dysregulation and apoptotic
death of vascular cells, elucidated by Catherine Shanahan.
These 2 investigators will collaborate on a review of these
topics and their interrelations.
Vascular calcium deposits are perhaps most rapidly fatal
when they accrue on the leaflets of the aortic valve. Calcific
aortic stenosis has unique consequences and mechanisms that
involve valvular interstitial cells and leaflet stiffening. Experts Jordan Miller, Don Heistad, and Robert Weiss will
review this disease process.
Paradoxically, atherosclerotic calcification and osteoporosis are associated even after adjustment for age. This has been
Vascular Calcification
1379
attributed to reciprocal effects of oxidatively modified atherogenic lipids, and resulting inflammation, on osteogenesis and
osteoclastogenesis in both arteries and skeletal bone. Linda
Demer and Yin Tintut will review these issues, as well as the
potential for cellular resorption and remodeling of calcific
vasculopathy.
In biomineralization, mechanical interactions between cells
and their matrices dramatically influence progression or
regression. Matrix stiffness clearly impacts the cellular fates
adopted by multipotent mesenchymal progenitors.9 Craig
Simmons will review the role of substrate compliance and
matricrine cues on the osteogenic programming of vascular
cells.
The normal calcium-phosphate product in serum and
interstitial fluids is close to, and often in excess of, the
threshold for spontaneous crystallization. Analogous to the
lipoprotein particles that ferry otherwise insoluble lipids,
fetuin-containing calciprotein particles possessing fetuin
regulate solubility and deposition of calcium salts. How
petrifaction is held off by hepatic ally–produced serum
proteins such as fetuin A will be addressed by Willi
Jahnen-Dechent and Markus Ketteler, who discovered and
pioneered the clinical relevance of fetuin biology to soft
tissue mineralization.
The process of vascular mineralization may be visualized
in vivo with new molecular imaging techniques that implement near-infrared fluorescence imaging. Matrix metabolism
and calcification can be coregistered with specific inflammatory cell infiltrates and osteogenic gene programs. Elena
Aikawa will review these novel approaches.
An emerging concept from this growing field is that
treatments for osteoporosis and atherosclerosis— calcium
supplements, calciotropic hormones, statins, angiotensin signal modifiers, ␤-blockers, and osteoporosis pharmacotherapies—should be expected to interact. Indeed, in a very recent
analysis from MESA, the Multiethnic Study of Atherosclerosis, aminobisphosphonate treatment for osteoporosis was
associated with decreased prevalence of vascular calcification
in older individuals but increased cardiovascular calcification
in younger patients!10 The goal of this thematic review series
is to highlight what is known concerning the biological
“players” and “game rules” with respect to vascular mineral
metabolism. Armed with this understanding, in the future it is
hoped that findings such as those of Bolland et al1 and
Elmariah and colleagues10 may be anticipated and considered
as therapeutic strategies are crafted, to the benefit of human
health and healthcare.
Sources of Funding
Supported by National Institutes of Health grants HL069229
(D.A.T.), HL081138 (D.A.T.), HL088651 (D.A.T.), and HL081202
(L.L.D.). D.A.T. is also supported by the Barnes-Jewish Hospital
Foundation.
Disclosures
None.
References
1. Bolland MJ, Avenell A, Baron JA, Grey A, MacLennan GS, Gamble GD,
Reid IR. Effect of calcium supplements on risk of myocardial infarction
and cardiovascular events: meta-analysis. BMJ. 2010;341:c3691.
1380
Circulation Research
May 27, 2011
2. Bild DE, Folsom AR, Lowe LP, Sidney S, Kiefe C, Westfall AO, Zheng
ZJ, Rumberger J. Prevalence and correlates of coronary calcification in
black and white young adults: the Coronary Artery Risk Development in
Young Adults (CARDIA) Study. Arterioscler Thromb Vasc Biol. 2001;
21:852– 857.
3. Simon A, Giral P, Levenson J. Extracoronary atherosclerotic plaque at
multiple sites and total coronary calcification deposit in asymptomatic
men: association with coronary risk profile. Circulation. 1995;92:
1414 –1421.
4. Newman AB, Naydeck BL, Sutton-Tyrrell K, Feldman A, Edmundowicz
D, Kuller LH. Coronary artery calcification in older adults to age 99:
prevalence and risk factors. Circulation. 2001;104:2679 –2684.
5. Pollin TI, Damcott CM, Shen H, Ott SH, Shelton J, Horenstein RB, Post
W, McLenithan JC, Bielak LF, Peyser PA, Mitchell BD, Miller M,
O’Connell JR, Shuldiner AR. A null mutation in human APOC3 confers
a favorable plasma lipid profile and apparent cardioprotection. Science.
2008;322:1702–1705.
6. Guzman RJ, Brinkley DM, Schumacher PM, Donahue RM, Beavers H,
Qin X. Tibial artery calcification as a marker of amputation risk in
patients with peripheral arterial disease. J Am Coll Cardiol. 2008;51:
1967–1974.
7. Mohler ER III, Gannon F, Reynolds C, Zimmerman R, Keane MG,
Kaplan FS. Bone formation and inflammation in cardiac valves.
Circulation. 2001;103:1522–1528.
8. Hunt JL, Fairman R, Mitchell ME, Carpenter JP, Golden M, Khalapyan
T, Wolfe M, Neschis D, Milner R, Scoll B, Cusack A, Mohler ER III.
Bone formation in carotid plaques: a clinicopathological study. Stroke.
2002;33:1214 –1219.
9. Engler AJ, Sen S, Sweeney HL, Discher DE. Matrix elasticity directs
stem cell lineage specification. Cell. 2006;126:677– 689.
10. Elmariah S, Delaney JA, O’Brien KD, Budoff MJ, Vogel-Claussen J,
Fuster V, Kronmal RA, Halperin JL. Bisphosphonate use and prevalence of valvular and vascular calcification in women: MESA (the
Multi-Ethnic Study of Atherosclerosis). J Am Coll Cardiol. 2010;56:
1752–1759.
Downloaded from http://circres.ahajournals.org/ by guest on June 18, 2017
Thematic Series on the Pathobiology of Vascular Calcification: An Introduction
Dwight A. Towler and Linda L. Demer
Downloaded from http://circres.ahajournals.org/ by guest on June 18, 2017
Circ Res. 2011;108:1378-1380
doi: 10.1161/CIRCRESAHA.110.234419
Circulation Research is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright © 2011 American Heart Association, Inc. All rights reserved.
Print ISSN: 0009-7330. Online ISSN: 1524-4571
The online version of this article, along with updated information and services, is located on the
World Wide Web at:
http://circres.ahajournals.org/content/108/11/1378
Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally published
in Circulation Research can be obtained via RightsLink, a service of the Copyright Clearance Center, not the
Editorial Office. Once the online version of the published article for which permission is being requested is
located, click Request Permissions in the middle column of the Web page under Services. Further information
about this process is available in the Permissions and Rights Question and Answer document.
Reprints: Information about reprints can be found online at:
http://www.lww.com/reprints
Subscriptions: Information about subscribing to Circulation Research is online at:
http://circres.ahajournals.org//subscriptions/