We investigated the effects of sequential and prolonged exposure to high and low wall shear stress on arterial remodeling using a rabbit arteriovenous fistula (AVF) model. Blood flow was increased by approximately 17-fold to 20-fold when the AVF was open, and returned to normal when the AVF was occluded. Repeated opening and closing of the AVF resulted in sequential exposure of the artery to high and low wall shear stress. High flow and high wall shear stress induced arterial dilatation, elongation, and tortuosity, without intimal thickening. The common carotid artery was elongated 37% after 4 weeks of high flow, and was shortened 10% after 6 weeks of normal flow. Subsequent cycles of high flow induced less elongation, with less shortening after return to normal flow. Enlargement of the distal segment was more dramatic than in the proximal segment, despite exposure to the same volume of flow and the same initial high wall shear stress after creation of the AVF. The distal carotid segment enlarged more than did the proximal segment during each exposure to high flow. In segments of carotid artery exposed to low wall shear stress (<5 dynes/cm(2)) intimal thickening developed. These changes were maximal in the distal carotid segment, just before the AVF. Each cycle of low wall shear stress induced intimal thickening accompanied by medial hyperplasia. Intimal thickening was inhibited during periods of high flow when wall shear stress was high. Three cycles of flow alteration induced three layers of intimal thickening in the distal arterial segment, two layers of intimal thickening in the middle segment, and one layer of intimal thickening in the proximal segment. Long-term exposure to low wall shear stress induced severe intimal thickening and medial hyperplasia in different segments. Thus the response of the carotid artery afferent to an AVF varies along the length of the artery, with maximum enlargement, elongation, and tortuosity in the distal segment, just proximal to the AVF. Similarly, intimal thickening in response to low wall shear stress is maximal in the distal carotid artery. It appears that intimal thickening is related to local levels of low wall shear stress, and occurs when wall shear stress chronically falls to less than 5 dynes/cm(2).