On the Molecular Basis for Vascular Calcification

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ON THE MOLECULAR BASIS FOR VASCULAR CALCIFICATION D. W. URRY* A. Introduction The ancient dictum to which Wells referred in the first edition of Cowdry's Arteriosclerosis [1], that "a man is as old as his arteries," applies to an even greater extent in modern Western societies. In 1972, 52 percent of deaths in the United States resulted from the major cardiovascular diseases [2, p. 1018]. Calcification, lipid deposition, and mural thrombus formation are three major degenerative processes that occur increasingly in vascular tissues with advancing age. Arterial wall calcification begins early in life [3] and steadily increases with age [4, 5]. The primary site of calcification, as well as of lipid deposition, is the elastic fiber. This fact has led Robert, Robert, and Robert to state recently that "it is true that we have the age of our arteries. This means more or less that we have the age of their elastic fibers" [6]. As early as 1933 Wells, in his treatise on the chemistry of arteriosclerosis [1], emphasized: "The significance of the elastic fibers as the primary seat of calcification is demonstrated by the frequent extensive selective calcification of the internal elastic lamina of arteries . . . without involvement of other parts of the vessel wall." Lansing and Blumenthal, in a series of reports in the 1940s and 1950s, pointed to the role of calcium and the elastic tissue in the genesis of arteriosclerosis [7-11] with conclusions such as: "The intensity and rate of calcium deposition is directly proportional to the intensity and rate of the elastic tissue changes" [10] and "Calcium is apparently deposited quite specifically in or on elastic tissue in the media, and medial calcification and elastic tissue changes are more pronounced under artheromatous plaques than *Laboratory of Molecular Biophysics and Cardiovascular Research and Training Center, University of Alabama in Birmingham, Birmingham, Alabama 35294. This work was supported by the National Institutes of Health grant HL-1 1310. I am grateful to T. N. James for his encouragement and counsel and to many members of the Laboratory of Molecular Biophysics who have contributed to specific phases of the work, namely, B. C. Starcher, T. Ohnishi, M. M. Long, and B. A. Cox. And to W. T. Kirby, Jr., a very special thanks for his contributions to the continuity of this research program. 68 I D. W. Urry · Vascular Calcification elsewhere in the same vessel" [9].1 These authors concurred with Wells, that "it would seem that the changes of arteriosclerosis appear whenever the elastic elements of the media yield permanently. . . . With advancing age the capacity to regenerate damaged elastic tissue is apparently reduced " [I]. During the last decade Yu and Blumenthal [12-15] and Eisenstein et al. [16] continued studies on calcification of elastic fibers. In a most impressive study on in vitro calcification of the aorta, Martin and colleagues [17] demonstrated that hydroxyapatite crystals "were localized almost exclusively in elastin." These are examples of an extensive literature from many laboratories over the period of nearly half a century, all pointing to the elastic fiber as the principal site of calcification in the arterial wall. In a recent review of Selye's book, Calciphylaxis [18], Urist stated: "The nature of the local mechanism of calcification is one of the most important unsolved problems of biochemistry" [19]. In his 1911 Harvey Lecture on calcification and ossification, Wells [20] not only reviewed the theories then prevalent on the local mechanism of calcification, but also set the stage for research efforts for an ensuing 60 years of seeking to identify the organic Kalkfanger. The Kalkfanger hypothesis for the initiation of calcification was one of "acid radicals formed within the tissues combining with and precipitating the calcium contained in the blood and tissue fluids" [20]. After considering and discounting phosphoric acid, sulfuric acid, and carbonic acid, Wells indicated that the search "must fall back on a possible organic Kalkfanger." Wells discussed in considerable detail and then discredited the fatty acids (calcium soaps) as improbable. The sulfates and carboxylates of mucopolysaccharides; the phosphates of phosphoprotein; and the carboxyl, amino, and sulfide groups of proteins—all organic Kalkfängers—have their modern-day proponents for the sites of calcium ion binding in...

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