Partial Off-Loading of Longitudinal Tension Induces Arterial Tortuosity

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 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. ...

Hemodynamics and Axial Strain Additively Increase Matrix Remodeling and MMP-9, But Not MMP-2, Expression in Arteries Engineered by Directed Remodeling

“…In contrast, when only hemodynamics was altered, MMP-9 expression was more strongly expressed in the endothelial=IEL region, suggesting that the MMP expression was being influenced more strongly by endothelial signaling. The spatial distribution of MMP expression is consistent with in vivo observations that endothelial denudation blocks MMP-mediated inward remodeling caused by decreased flow 29 but not remodeling due to decreased 24 or increased 23 axial loading. The combination of mechanical stimuli appears to express MMP equally throughout the artery wall while also demonstrating strong nuclear staining, seemingly combining the presentation profiles of the individual stimuli.…”

“…19 Specifically, increased MMP-2 and MMP-9 expression has been demonstrated in response to altered blood flow 20,21 and hypertension, 22 while altered axial strain caused sustained MMP-2 expression but only transient MMP-9 expression 23,24 in arteries in vivo. Altered shear stress also produces soluble factors such as nitric oxide (NO) 25 that lead to MMP production and release in an NF-kB (p50=p65 subunit)-dependent response.…”

Regional variation in arterial stiffening and dysfunction in Western diet-induced obesity

“…Reduced carotid artery fenestra number and size have been reported in spontaneously hypertensive rats prior to the onset of hypertension (1,9) and in rabbits after chronic flow reduction (50). Conversely, carotid fenestra enlargement has been reported following chronic reductions of longitudinal tension (20). These data suggest that hemodynamic and mechanical forces may be dynamic regulators of IEL ultrastructure and stability.…”

Retinal vascular tortuosity in persons with diabetes and diabetic retinopathy

“…In persons with diabetes, hyperglycaemia-mediated hypoperfusion can initiate blood flow disturbance together with the loss of endothelium cells and pericytes of the vessel wall, leading to the loss of autoregulatory function of the vessels including its compensatory mechanisms for the fluctuating hydrostatic pressure [25]. This impaired autoregulation of blood vessels could result in an undermined basement membrane and the failure to maintain the stability of the vessel wall against irregular longitudinal traction and transmural pressure [26,27]. Subsequently, vessels become dilated and tortuous.…”