SMOOTH MUSCLE CELL SENESCENCE IN AORTIC ANEURYSMS

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The goals of this research program are to determine how cellular senescence and disease-specific changes in the growth capacity of vascular smooth muscle cells (SMC) may be related to distinct patterns of age-related degeneration in the human aorta. Whereas atherosclerosis is associated with intimal SMC proliferation and matrix deposition, aortic aneurysms are principally characterized by degeneration of the media. This includes proteolytic degradation of the structural matrix proteins, elastin and collagen, as well as a decrease in SMC density, evidence of SMC apoptosis, and increased SMC production of the tumor-suppressor proteins, p53 and p21. By depleting a cell population otherwise capable of directing matrix repair, the loss of medial SMC may be particularly significant in aortic aneurysms. Aneurysm-derived SMC in culture exhibit a limited growth capacity compared to SMC derived from normal aortas or atherosclerotic lesions, a pattern not solely dependent on donor age. Sustained phenotypic alterations affecting the growth capacity of vascular SMC, possibly reflecting accelerated cellular senescence and/or an increased susceptibility to apoptosis, may thereby contribute to different but related patterns of human aortic pathology. Using tissues from normal and diseased human vessels, this proposal seeks to elucidate the characteristics of aneurysm-derived SMC through the following specific aims: (I) establish if the impaired growth of aneurysm-derived SMC is due to accelerated cellular senescence and/or an increased rate of apoptosis compared to SMC derived from control tissues; (2) determine if the growth characteristics of aneurysm.derived SMC are transferable to normal SMC through a soluble intermediate or changes in matrix composition; and (3) characterize how aneurysm-derived SMC respond to mitogen stimulation with respect to (a) c-fos and other early-response genes that promote cell proliferation, (b)p53, and (c) p2l and other genes regulating cell cy~e progression. These studies will help to fill important gaps in knowledge regarding the relationships between aging, cellular senescence and cell death in vascular disease, as well as to clarify the cellular and molecular mechanisms underlying various patterns of aortic degeneration.