International Stroke Conference Oral Abstracts
Session Title: Vascular Biology in Health and Disease Oral Abstracts
Abstract 108: Cell-Specific Interference with Endothelial PPARγ Produces Oxidative Stress and Accelerates Vascular Aging
Despite the fact that aging is the greatest risk factor for vascular disease and stroke, relatively little is known regarding mechanisms that promote or protect against vascular aging in experimental models or people. Endothelial dysfunction is a key contributor to both the initiation and progression of vascular disease. Atherosclerosis in carotid arteries (carotid artery disease) greatly increases the risk for ischemic stroke and may contribute to dementia (including Alzheimer’s disease). Peroxisome proliferator activated receptor-γ (PPARγ) is a ligand-activated transcription factor that exerts diverse effects depending on the cell type. Recent work suggests that PPARγ can have beneficial effects in the vasculature including protection against oxidative stress. Relatively little is known regarding the potential role of PPARγ in aging. We used transgenic mice expressing a dominant negative mutation in human PPARγ (V290M) under control of the endothelial-specific vascular cadherin promoter (designated E-V290M) to examine the hypothesis that interference with endothelial PPARγ will promote age-induced vascular dysfunction. Responses of carotid arteries from adult (6±1 mo) and old (23±1 mo) E-V290M mice and non-transgenic littermates (controls) were examined in vitro. Acetylcholine (an endothelium-dependent agonist) produced similar relaxation of arteries from adult control and E-V290M mice as well as old control mice. In contrast, responses to acetylcholine in arteries from old E-V290M mice were markedly impaired. For example, relaxation of the carotid artery to 10 µmol/L acetylcholine was 84±3 and 40±6% in old control versus old E-V290M mice, respectively (P<0.01). The impaired response to acetylcholine in old E-V290M mice could be restored to normal (81±4% relaxation) by tempol, a scavenger of superoxide. Relaxation of the carotid artery to nitroprusside (a nitric oxide donor that acts directly on vascular muscle) was similar in all groups. These findings provide the first evidence that age-related vascular dysfunction is accelerated following cell-specific interference with endothelial PPARγ function. The mechanism that accounts for this change appears to involve reactive oxygen species. Our findings suggest a major protective role for endothelial PPARγ in age-induced oxidative stress and vascular dysfunction.