Decreased blood vessel contractility and increased blood pressure occur with aging. The aorticI thickening associated with atherosclerosis, inflammation, hypertension, and aging is primarily duel to vascular smooth muscle cell (VSMC) hypertrophy. This, in turn, results from an increase in DNA content of VSMC, yielding polyploid cells. We found a remarkably robust hyperbolic relation between rat age and the ratio of tetraploid to diploid aortic VSMC. Approximately 60% of VSMC from 36 month old rats are tetraploid, while 25% of VSMC from 24 month old rats and only 8% from 3 month old rats are tetraploid. We hypothesize that these tetraploid VSMC are functionally distinct from diploid cells. We have developed a method for separating diploid aortic VSMC from cells with higher ploidy. In preliminary studies, we found that expression of the cell cycle regulator, p21 is elevated in higher ploidy cells, as occurs in other cell types with aging, implying that ploidy likely impacts the proliferative potential of VSMC. We found that expression of receptors known to modulate calcium mobilization is reduced in tetraploid aortic VSMC isolated from old animals. We will test the functional relevance of the large increase in tetrapoid cells that occurs with aging in the following Specific Aims.
Aim 1 is to test the cell dynamic impact of accumulation of tetraploid cells by determining the proliferative potential and apoptotic rates of aortic diploid and tetraploid VSMC derived from old rats. This is relevant to events that are responsible for VSMC accumulation.
Aim 2 is to determine differences in calcium mobilization between diploid and tetraploid aortic VSMC derived from old rats. This is important since calcium flux, a key determinant of smooth muscle contractility, is important in the genesis of hypertension, a common condition in the elderly.
These Aims will test the impact and relevance of the large increase in VSMC tetraploidy with aging and will point to relevant directions to be pursued in further mechanistic studies.
| Yang, Dan; McCrann, Donald J; Nguyen, Hao et al. (2007) Increased polyploidy in aortic vascular smooth muscle cells during aging is marked by cellular senescence. Aging Cell 6:257-60 |
| Nagata, Yuka; Jones, Matthew R; Nguyen, Hao G et al. (2005) Vascular smooth muscle cell polyploidization involves changes in chromosome passenger proteins and an endomitotic cell cycle. Exp Cell Res 305:277-91 |
| Jones, Matthew R; Ravid, Katya (2004) Vascular smooth muscle polyploidization as a biomarker for aging and its impact on differential gene expression. J Biol Chem 279:5306-13 |
