Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in the United States and is projected to become the leading cause of mortality in the world. Atherosclerosis is the most important single factor contributing to this disease burden. In this study, we characterize relationships between endothelial dysfunction and vascular disease in an animal model of diet-induced, early-stage atherosclerotic vascular disease. We tested the hypothesis that hypercholesterolaemia induces vascular disease and impairs endothelium-dependent relaxation (EDR) in conduit arteries of adult male Yucatan pigs. Pigs were fed a normal fat (NF) or high fat cholesterol (HFC) diet for 20-24 weeks. Results indicate that, while the HFC diet did not alter EDR in femoral or brachial arteries, EDR was significantly decreased in both carotid and coronary arteries. Sudanophilic fatty streaks were significantly present in the abdominal aorta and common carotid artery. Histopathology revealed increased intima-media thickness (IMT) and foam cell accumulation in Stary Stage I-III lesions in the abdominal aorta, common carotid artery and femoral arteries. In the coronary arteries, the accumulation of foam cells in Stary Stage I and II lesions resulted in a trend for increased IMT. There was no evidence of vascular disease in the brachial arteries. These results indicate that early stages of CVD (Stary Stage I-III) precede decreases in EDR induced by HFC diet, because femoral arteries exhibited foam cell accumulation and an increased IMT but no change in endothelial function.

2025 Hyperlipidemia leads to carotid intima-medial thickening in Yucatan miniature swine while exercise training attenuates this response. PURPOSE: We hypothesized that hyperlipidemia would lead to carotid endothelial dysfunction and that exercise training would prevent and/or attenuate loss of endothelial function. METHODS: Male Yucatan miniature swine were fed a high fat diet for 20 weeks, (2% cholesterol by weight) in which 46% of their kilo-calories were derived from fat. A progressive exercise training program was started 4 weeks after the high fat diet was initiated and involved sprint and endurance treadmill running for 16 weeks. Carotid endothelial function was characterized with the endothelial dependent dilator bradykinin (BK) in the presence or absence of L-NAME and Indomethacin, nitric oxide synthase and cycloxygenase inhibitors respectively. RESULTS: Bradykinin induced dilation was significantly attenuated in hyperlipidemic swine (p = 0.05). However, exercise training did not prevent/attenuate the loss of endothelial function (p = 0.40). Interestingly, in denuded vessels, BK elicited a constrictive response with the greatest constriction produced in high fat exercise trained vessels. Further, endothelial independent dilation to sodium nitroprusside, a nitric oxide donor, was attenuated in exercise trained pigs at higher doses (p = 0.01). The increase in constrictor response of vascular smooth muscle to BK in trained high fat fed pigs and the decrease in NO sensitivity may explain why exercise training did not augment endothelial function in hyperlipidemic swine. Inhibitor data with L-NAME suggests that nitric oxide played a significant role in BK induced dilation; however, the relative contribution of nitric oxide was similar in sedentary, trained, normal and high fat fed pigs. Indomethacin data suggests that prostanoids do not play a significant role in BK induced dilation. CONCLUSIONS: These data suggest that hyperlipidemia attenuates carotid endothelial responses to BK induced dilation in male Yucatan miniature swine, secondary to a reduction in a non-NOS/non-COX mediator, perhaps EDHF. (Supported by NIH grant # HL-52490).