Vascular Smooth Muscle Cell Polyploidy: An Adaptive or Maladaptive Response? DONALD J. MCCRANN, HAO G. NGUYEN, MATTHEW R. JONES, AND KATYA RAVID * Department of Biochemistry and Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Massachusetts Polyploidy is a state in which a cell contains multiple copies of its entire genome, while a normal diploid cell contains only two sets of homologous chromosomes. Although widely studied and pervasive in nature, the signals and mechanisms of polyploidization and its accompanying operational consequences are still unclear. This review focuses on relevant questions in deciphering the regulation of polyploidization of vascular smooth muscle cells (VSMC) in mammals and the role of polyploidy in various vascular pathologies, such as hypertension and aging. Additionally, we will explore new investigations in polyploidization of VSMCs involving the rapidly expanding fields of oxidative stress and senescence. J. Cell. Physiol. 215: 588–592, 2008. ß 2008 Wiley-Liss, Inc. Polyploidy is a condition in which cells contain multiple copies of their entire genome, whereas normal diploid cells only contain two sets of homologous chromosomes (2N) (Ravid et al., 2002). The DNA content of a polyploid cell can range from 4N, 8N, 16N to greater than 128N. Depending on the organism, cell-type, and specific physiological setting, the accumulation of multiple copies of the genome may come from a variety of mechanisms, mainly DNA synthesis without division into daughter cells and cell fusion. The former mechanism contains a couple of subgroups, including: DNA synthesis followed by a truncated M-phase, or a failure of cytokinesis (as reviewed in Ravid et al., 2002 and Zimmet and Ravid, 2000). The observation and definition of these various polyploidy cell cycles illustrates the potential variation in mechanisms of polyploidization and may also be reflective of its causes. Polyploidy is a frequent phenomenon in lower organisms, including plant, insect, fungi, invertebrate, fish, amphibian, and the lower vertebrates (Comai, 2005). Higher vertebrates and mammals do not tolerate polyploidy as a pervasive state, in such that germ-line polyploidy is almost certain to result in embryonic lethality (although the first ever polyploid mammal was recently discovered in Argentina) (Gallardo et al., 1999; Benzacken et al., 2001; Comai, 2005). However, somatic polyploidy is often found in normal tissues including liver parenchyma, heart muscle cells, and the platelet progenitor-megakaryocytes, and is required for their function (Zimmet and Ravid, 2000). Hepatocytes, vascular smooth muscle cells (VSMC), and cardiac myocytes in addition to many other cell types have all been shown to develop a certain degree of polyploidy during a normal lifespan (Ravid et al., 2002). In contrast to megakaryocytes, the state of polyploidization in these cells is more frequently coupled to decreased organ function and conditions of stress rather than part of its natural process of terminal differentiation and cellular function (Gorla et al., 2001; Nagata et al., 2005). Certain tissues are also found to foster polyploid cell development under conditions of stress, for example, uterine smooth muscle cells during pregnancy (van der Heijden and James, 1975), thyroid cells during hyperthyroidism (Gilbert and Pfitzer, 1977; Auer et al., 1985) and in the seminal vesicles with aging (Mohr et al., 1974). Central to the discussion of the functional significance of polyploidy is the nature of the polyploidization event. Is the polyploidization event consequent of a mitotic failure caused by insult to a proliferating cell? Or, despite an overall association with decreased organ function in some tissues, is the polyploidization event a deliberate process conferring advantages over maintaining a diploid status? Examples of each of these have been described and exist in nature, yet it remains unclear the exact nature of polyploidization of VSMCs within the vasculature. The following discussion will explore these questions in the context of the regulation of ploidy in VSMCs with respect to hypertension and aging. In addition, we will discuss more recent investigations linking polyploidization, the involvement of oxidative stress, and cellular senescence. VSMC Polyploidy The existence of polyploid VSMCs was first reported in rat VSMCs in association with hypertension models (Owens and Schwartz, 1982). They and others have since reported that in chronically hypertensive animals, nearly 50% of the smooth muscle cells in the vessel wall contain a DNA ploidy content of greater than 2N (Owens, 1985, 1989). It has been described that polyploid hypertrophied smooth muscle cells displaying increased protein synthesis are responsible for vessel thickening at capacitance arteries in hypertension, and that hyperplasia is not a significant factor in medial thickening (Olivetti et al., 1980; Owens et al., 1981). Hyperplasia, which is characterized by an increase in VSMC proliferation, occurs during atherosclerosis and plaque development (Matturri et al., 1997). The artery wall is composed of three main cell tissue layers, beginning with the innermost layer next to the lumen, the intima, the media, and the adventitia. Atherosclerotic plaques are characterized by invasion and proliferation of smooth muscle cells from the media layer into the intima layer. Interestingly, atherosclerotic plaques in the human artery wall were described to contain a small, but significant decrease in tetraploid nuclei in comparison to the underlying media, while comparisons of normal intima to the underlying media did not show such changes (Barrett et al., 1983; Matturri et al., 2001). As hypertrophy is not reportedly observed in atherosclerotic Established investigator with the American Heart Association. *Correspondence to: Katya Ravid, Department of Biochemistry, K225, Boston University School of Medicine, Boston, MA 02118. E-mail: ravid@biochem.bumc.bu.edu Received 23 August 2007; Accepted 31 October 2007 DOI: 10.1002/jcp.21363 REVIEW ARTICLE 588 Journal of Journal of Cellular Physiology Cellular Physiology ß 2008 WILEY-LISS, INC.