Partial Off-Loading of Longitudinal Tension Induces Arterial Tortuosity

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Abstract
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 62±2% to 33±2% 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. We used interposition grafts to demonstrate that only partial off-loading of longitudinal arterial strain initiates arterial growth and tortuosity. Wall growth and remodeling comprised cell proliferation and apoptosis and extracellular matrix accumulation and remodeling. Surprisingly, (metalloproteinase-dependent) tortuosity occurred despite the persistence of significant longitudinal strain.