AGING, ESTROGEN, CELL SENESCENCE AND VASCULAR INFLAMMATION



Anne Knowlton, M.D., University of California, Davis, CA, USA

Aging is characterized by the development of systemic inflammatory changes, organ dysfunction and frailty. In females, loss of estrogen compounds these changes. Estrogen loss combined with aging leads to increased oxidative stress, increased inflammation, dysfunctional EPCs leading to impaired vascular repair, increased inflammation and increased monocyte adhesion. Cellular senescence was thought to be benign, but it is now evident that senescent cells are pro-inflammatory and may be associated with deleterious consequences in aging organisms that accumulate senescent cells. Senescent endothelial cells secrete more pro-inflammatory factors than non-senescent cells, and more disturbingly, may also incite pro-inflammatory secretion by healthy non-senescent cells along with other negative functional changes. We hypothesized that cell senescence, which increases with aging, is an important contributor to inflammation and vascular dysfunction seen with aging, and that prevention or reduction in cell senescence can mitigate the inflammatory changes associated with estrogen loss and aging. A corollary to this hypothesis was that 17beta-estradiol (E2) will mitigate aging changes. To investigate this issue, we co-cultured human microvascular smooth muscle cells (VSMC) with senescent (SEN) or early-passage (EP) human endothelial cells (EC), separated by a permeable membrane to allow both VSMC and EC to communicate with secreted factors. We found that the coculture of VSMC with EC synergistically elevated secreted pro-inflammatory factors, IL-6, IL-8, and MCP-1. While both SEN and EP cells promoted the cytokine and chemokine release, the amount released in SEN EC – VSMC coculture was about 1.5- to 2- fold greater than with EP EC – VSMC. In addition, when E2 was added to culture, the phospho-VASP/VASP ratio increased. These findings support the potential role of senescent EC in aggravating hypertension and the persistent inflammatory disorder that are common in older individuals, as well as the potential of E2 in aged individuals to improve vascular function.