Atherosclerosis may lead to the development of a potentially occlusive fibrin-rich thrombus in the arterial circulation, which often manifests in a myocardial infarction or stroke. A primary factor thought to underlie such thrombotic events is endothelial dysfunction. The endothelium plays an important role in vascular health and the prevention of thrombosis through the regulation of fibrinolysis. Fibrinolysis is the process by which fibrous clots are enzymatically degraded into soluble degradation products. Endothelial cells regulate fibrinolysis through the synthesis and release of tissue-type plasminogen activator (t-PA), the primary enzyme that initiates fibrinolysis. Aging and a sedentary lifestyle are established cardiovascular and thrombotic disease risk factors. While the influence of aging and physical inactivity on plasma fibrinolytic markers, such as t-PA, is well characterized, the effect of sedentary aging on endothelial control of fibrinolysis is unknown. This is significant because it is the ability of the vascular endothelium to acutely release t-PA and not plasma concentrations that determines effective endogenous fibrinolytic potential. The purpose of this dissertation was to test the following associated hypotheses: (1) the capacity of the endothelium to release t-PA declines with age in healthy sedentary men but not habitually physically active men; (2) a program of regular aerobic exercise would at least partially reverse the postulated age-related reduction in endothelial t-PA release in previously sedentary older men; and (3) the ability of the endothelium to release t-PA is not dependent upon nitric oxide bioavailability. To test these hypotheses, we utilized an isolated forearm model to assess net endothelial t-PA release in vivo. To address hypothesis one, we studied 62 healthy men aged 22–35 or 50–75 years of age, who were either sedentary or endurance exercise-trained. Complimenting this cross-sectional study, we performed an exercise intervention to determine the direct effects of exercise on endothelial t-PA release. In attempt to better understand the endothelial mechanism of regulated t-PA release, we assessed the capacity of the endothelium to release t-PA during nitric oxide blockade. Results from these studies demonstrated that: (1) the capacity of the vascular endothelium to release t-PA declines significantly with age in healthy sedentary men but is well preserved with age in men who perform regular aerobic endurance exercise; (2) moderate aerobic exercise training (13 weeks of walking) can reverse the age-related decline in the capacity of the endothelium to release t-PA in previously sedentary middle-aged and older men; and (3) t-PA release is not dependent upon the availability of nitric oxide. Collectively these findings suggest that regular aerobic exercise may prevent and reverse the adverse effects of aging. This may represent an important vasculoprotective adaptation conferred by regular aerobic exercise.
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