Abstract-Changes in blood pressure or flow induce arterial remodeling that normalizes mechanical loads that are imposed on arterial tissue. Arteries are also under substantial longitudinal stretch (axial strain) that may be altered by growth or atrophy of tissues to which they are attached. We therefore tested whether axial strain is also regulated in a negative feedback manner through arterial remodeling. Axial strain in rabbit carotid arteries was increased from 62Ϯ2% to 97Ϯ2% without altering other mechanical loads on wall tissues. Strain was reduced within 3 days and completely normalized by 7 days. Remodeling involved tissue elaboration, endothelial cell replication rates were increased by Ͼ50-fold and smooth muscle cell replication rates were increased by Ͼ15-fold, and substantially elevated DNA, elastin, and collagen contents were recorded. Also, increased rates of apoptosis were indicated by degradation of DNA into oligonucleosomes, and matrix remodeling was reflected in enlarged fenestrae in the internal elastic lamina and increased expression and activation of gelatinases, especially matrix metalloproteinase-2. Intriguingly, reduced axial strain was not normalized, presumably because remodeling processes, apart from cell contraction, are ineffective in decreasing strain, and arterial smooth muscle orientation precludes large effects of contraction on axial strain.
Objectives-Arterial tortuosity is a frequent manifestation of vascular disease and collateral vessel growth, but its causes are poorly understood. This study was designed to assess the relationship between the development of tortuosity and the mechanical forces that are imposed on arterial tissue. Methods and Results-Axial strain in rabbit carotid arteries was reduced from 62Ϯ2% to 33Ϯ2% by implanting an interposition graft, prepared from the contralateral carotid, at the downstream end of the artery. Axial strain remained unchanged for 12 weeks; however, all vessels became tortuous because of tissue growth and remodeling. After 7 days, there was a marked elevation in proliferation rates of endothelial and smooth muscle cells; however, increased apoptosis was also detected, and no net accumulation of DNA was observed. Significant accumulations of elastin (24%) and total collagen (26%) occurred by 5 weeks. Gelatin zymography detected upregulation and activation of matrix metalloproteinase-2 (MMP-2), and confocal microscopy revealed enlargement of fenestrae in the internal elastic lamina. MMP inhibition by treatment with doxycycline prevented enlargement of fenestrae and development of tortuosity, and it enabled normalization of axial strain by 5 weeks. Conclusions-These findings indicate that substantial axial strain is necessary to sustain the morphological stability of arteries, and that a reduction in strain results in arterial tortuosity attributable to aberrant MMP activity. Key Words: peripheral vasculature Ⅲ vascular biology Ⅲ tortuosity Ⅲ remodeling Ⅲ metalloproteinase A rteries often become tortuous in response to potent and persistent growth stimuli. For example, collateral vessels that expand after coronary or peripheral arterial occlusion often assume a meandering path; indeed, the presence of tortuosity is frequently used to identify these arteries. 1 In addition, vessel wall hypertrophy associated with persistent hypertension frequently induces extreme tortuosity of central arteries, including the descending aorta, in the aged. 2 Development of tortuosity is important because it represents a futile component of arterial growth that elevates flow resistance, it compromises the capacity of arteries to remodel appropriately in response to additional growth stimuli, 3 and the flow disturbances it produces may predispose the vessel to atherogenesis. 4 See page 892The causes of vessel tortuosity are unclear. The simplest explanation is that arterial growth inevitably involves some longitudinal elaboration of new tissues. Because the origins of most arteries at parent vessels and their terminations at daughter branches are anatomically fixed, longitudinal growth may ultimately force vessels to become tortuous. Tortuosity is generally seen only with very potent growth responses, but this may be because most arteries exhibit substantial in situ axial stretch of 40% to 60%. 5 Consequently, it is possible that longitudinal tissue elaboration must first off-load this axial strain before tortuosity is manifest. ...
Background-Chronic total occlusions (CTOs) are associated with significant angina, impaired left ventricular function, and worse long-term outcomes. Percutaneous coronary interventions in CTO are unsuccessful in up to 50% of cases, primarily because of inability to cross the lesion with a guide wire. Collagen is the predominant component of the atherosclerotic plaque. The objective of this study was to determine the efficacy and toxicity of local delivery of a collagen-degrading enzyme to facilitate guide wire crossing in CTO. Methods and Results-Type IA collagenase (100 or 450 g) or placebo was locally administered to 45 CTOs in a rabbit femoral artery model. Mean occlusion duration was 16Ϯ5 weeks. Attempts to cross the CTO (mean length, 28Ϯ9 mm) with conventional guide wires were assessed at 72 hours after treatment. An additional 3 arteries per group were assessed for collagenase effects at 24 hours after treatment. Successful guide wire crossings were significantly higher in collagenase-treated arteries (13 of 21, 62%) than in placebo-treated arteries (7 of 24, 29%) (Pϭ0.028). No adverse effects on arterial structure were observed in collagenase-treated arteries.
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