Flow-induced changes in vessel caliber tend to restore baseline wall shear stress (WSS) and have been reported to be endothelium-dependent. To investigate the role of endothelium-derived nitric oxide (NO) in the adaptive increase in artery diameter in response to a chronic increase in blood flow, an arteriovenous fistula was constructed between the left common carotid artery (CCA) and the external jugular vein in 22 New Zealand White rabbits, and NO synthesis was inhibited in 14 animals by long-term administration of NG-nitro-L-arginine-methyl ester (L-NAME) in drinking water given for 4 weeks. The remaining 8 animals served as controls. Mean arterial blood pressure was not significantly altered by L-NAME treatment (91 +/- 2 in control versus 98 +/- 3 mm Hg in L-NAME-treated rabbits). Blood flow significantly increased in the left CCA in both groups but was lower in L-NAME-treated than control animals (106.1 +/- 10.7 versus 196.2 +/- 32.3 mL/min, P < .003). The diameter of the flow-loaded left CCA also increased significantly in both groups compared with the right CCA (2.15 +/- 0.12 and 2.54 +/- 0.1 mm, respectively, P < .02), but the increase was less in the L-NAME-treated than the control group (3.24 +/- 0.09 and 4.64 +/- 0.17 mm, respectively, P < .0001). The diameter of the anastomosed veins was also increased but to a much lesser degree in L-NAME-treated animals than in controls (4.14 +/- 0.29 versus 7.94 +/- 0.51 mm, P < .0001). As a result of artery enlargement, WSS was normalized in the flow-loaded left CCA of the control group (8.87 +/- 0.77 dynes/cm2) regardless of blood flow values. In L-NAME-treated animals, however, WSS was only partially regulated, the mean value being significantly increased (18.7 +/- 2.2 dynes/cm2, P < .006). Moreover, a highly significant positive correlation between WSS and blood flow was obtained in L-NAME-treated animals (r = .84, P < .0001). We also found remodeling of the artery wall, with a larger increase in the medial cross-sectional area associated with an increased number of smooth muscle cells, in the control group compared with the L-NAME-treated group (0.75 +/- 0.09 versus 0.49 +/- 0.04 mm2 and 4504 +/- 722 versus 2717 +/- 282 cells/mm2, P < .03). We conclude that NO plays a role in the increase of vessel caliber in response to chronic increase in blood flow. As yet unidentified additional metabolic processes appear to be necessary for a complete regulatory response.

Abstract-Tears in the internal elastic lamina (IEL) can be observed after chronic increases in arterial blood flow, suggesting a potential role for matrix metalloproteinases (MMPs) in flow-induced vascular remodeling. We undertook to study this phenomenon by constructing an arteriovenous fistula (AVF) between the left common carotid artery (CCA) and the external jugular vein in rabbits. The diameter of the flow-loaded left CCA increased by 13.6Ϯ1.8% by day 3 after construction of the AVF compared with the right CCA (nϭ4, PϽ0.01) and by 40.7Ϯ7.5% by day-15 (nϭ10, PϽ0.0001). Increased CCA diameter also coincided with IEL fragmentation. Three days after construction of the AVF, gelatin zymography of protein extracts from left CCAs of untreated rabbits showed a significant increase in the 62-kDa (active MMP-2) activity and the appearance of a lytic band at 92 kDa (pro-MMP-9). In further experiments, MMP activity was inhibited by treatment with doxycycline (DOX) or BB-94, a specific MMP inhibitor. The increase in the 62-kDa gelatinolytic band was abolished in DOX-and BB-94 -treated rabbits. The 92-kDa gelatinolytic band was also reduced in DOX-treated animals. Furthermore, both increased left CCA diameter and IEL fragmentation were abolished in DOX-and BB-94 -treated rabbits. To evaluate whether nitric oxide was involved in blood flow-induced MMP activation, the rabbits were treated with N G -nitro-L-arginine methyl ester to inhibit nitric oxide synthesis. MMP activities were significantly decreased in the left CCAs of Key Words: wall shear stress Ⅲ vascular remodeling Ⅲ matrix metalloproteinases C hronic increases in arterial blood flow elicit an adaptive response of the arterial wall, characterized by the reorganization of cellular and extracellular components and leading to arterial enlargement and a reduction in wall shear stress (WSS) to physiological baseline values. [1][2][3][4] There is evidence that the endothelium plays an essential role in this adaptive process. 3,5 In models of arteriovenous fistula (AVF), endothelial denudation abolishes arterial diameter growth, 3 and we have shown that chronic inhibition of nitric oxide (NO) production by N G -nitro-L-arginine methyl ester (L-NAME) treatment inhibits, at least partially, the adaptive WSS regulation in flow-loaded vessels. 4 However, the mechanisms by which the endothelium or endothelium-dependent NO operates to induce arterial wall remodeling are not understood. Interestingly, disruption of the extracellular matrix with tears of the internal elastic lamina (IEL) can be observed in this model, which suggests a potential role for matrix metalloproteinases (MMPs) in matrix digestion and reorganization, leading to arterial wall remodeling, 4,6 -11 and for NO in MMP activation. 12 This study was therefore designed to examine the effects of chronic in vivo inhibition of MMPs by treatment with BB-94, a specific MMP inhibitor, or doxycycline (DOX), on vascular remodeling of the common carotid artery (CCA) in a rabbit model of AVF. We also evaluated the effect...

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