Central Arterial Aging: Humans to Molecules

Project: Research project

Description

The structure and function of central arteries change throughout the lifetime of humans. An understanding of how the arterial wall ages is crucial not only because of its profound effects on arterial and cardiac structure and function, but also because the central artery, remodeled by aging, sets the stage for arterial diseases. It is well known that the diffuse intima thickening is a hallmark of the central arteries that accompanies advancing age, but the molecular mechanisms remain poorly understood. A series of studies on arterial aging in rodents, nonhuman primates, and humans have been performed in our group. In Fisher 344 corssbred Brown Norway rats (FXBN), the marked age-associated increases in the angiotensin II (Ang II) protein, martix metalloproteinase-2 activation (MMP-2), and transforming growth factor-B1 (TGF-B1). Are observed within the thickened arterial intima, including infiltrated vascular smooth muscle cells (VSMCs) and deposited collagen and fibronectin (FN). Interestingly, in older male monkeys, an upregulation of both Ang II and MMP-2 is detected in the thickened aortic intimae, contining numerous VSMC and collagen. Notably, we also found that both Ang II and MMP activity are upregulated in the thickened arterial intima of humans in areas remote from atherosclerotic plaques with aging. Thus, Ang II and MMP-2 accompany age-associated arterial remodeling. To analyze this relationship, we infused Ang II into young rats. An administration of Ang II to young rats increases arterial MMP-2 and TGF-B1 activity, intima infiltration by VSMCs, and collagen deposition. This reproduces nearly all of the aforementioned structural and molecular features of the arterial wall in young rats that have been observed in older rats. Furthermore, TGF-B1 activation is dependent, in part at least, by a concomitant age-associated increase in MMP-2 activity; and monocyte chemoattractant protein-1 (MCP-1), a downstream molecule of Ang signaling, is markedly increased within the older aortic wall in rats. These findings point at a central role for Ang II and associated signaling molecules in arterial aging. MMP-2, MCP-1, TGF-B1, collagen and FN production are all downstream events of Ang II-AT1 receptor signaling. The age-associated increases of these related molecules within the older remodeled aorta implicate local arterial Ang II signaling pathways as targets for prevention or amelioration of arterial remodeling, and its attendant risk for the incidence and severity of arterial diseases that increase exponentially with advancing age.
StatusFinished
Effective start/end date8/1/997/31/04

Funding

  • National Institutes of Health: $129,330.00
  • National Institutes of Health: $107,688.00
  • National Institutes of Health
  • National Institutes of Health: $129,330.00
  • National Institutes of Health: $123,984.00

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ASJC

  • Medicine(all)