THEMATIC SERIES ON THE PATHOBIOLOGY OF VASCULAR CALCIFICATION: AN INTRODUCTION

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.

In a recent meta-analysis from New Zealand¹, Bolland, Reid and colleagues reported that dietary calcium supplementation is associated with a significant increase in risk for myocardial infarction. While 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 elderly. However, its prevalence actually corresponds roughly with age, with coronary calcification occurring in about 20% of young adults, about 60% of those in middle age, and about 90% of the elderly.^2–4 Moreover, coronary calcification is now widely used as the preferred marker for the earliest “subclinical” phase of atherosclerosis⁵. Additionally, implementation of tibial artery calcification scoring portends lower extremity amputation risk, outperforming traditional methods of evaluation such as ankle-brachial indices⁶. Clearly, the burgeoning unmet clinical needs in cardiovascular medicine will require a better understanding of the molecular mechanisms controlling the initiation and progression of vascular mineralization.

Consistent with this need, our understanding of how arterial tissues undergo this mineralizing transformation has rapidly grown, 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 1996–1999; 15 in 2000; about 75 per year from 2001–2004; and about 150 per year from 2005–2009. 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 (i.e., 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 driving cardiovascular mineralization overlap with those driving embryonic osteogenesis and post-natal skeletal repair. Key factors include potent morphogens that activate osteogenic BMP and Wnt 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 man and our 21^st century lifestyle. Aortic wall calcification was detected by CT scan of a natural mummy found in ice floes of the Alps. The remains were estimated to be from 5300 years ago. In this series, Robert Terkeltaub and Frank Rutsch will review the molecular genetics that predispose or protect humankind from vascular calcification --- colleagues who identified the gene defect responsible for the previously mysterious disorder, generalized arterial calcification of infancy.

The most severe calcific vasculopathy occurs in patients with chronic kidney disease, particularly those requiring dialysis where 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 two 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, involving 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 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 progenitors⁹. 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 using new molecular imaging techniques that implement near infrared fluorescence imaging. Matrix metabolism and calcification can be co-registered 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, beta-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 Halperin and colleagues¹⁰ may be anticipated and considered as therapeutic strategies are crafted, to the benefit of human health and healthcare.

Non-standard Abbreviations and Acronyms

BMP

bone morphogenetic protein

CT

computed tomography

MESA

Multiethnic Study of Atherosclerosis

PubMed

http://www.ncbi.nlm.nih.gov/pubmed

Wnt

wingless-type MMTV integration site family member.