Effects of Cyclic Flexure on Endothelial Permeability and Apoptosis in Arterial Segments Perfused Ex Vivo

Abstract

Certain arteries (e.g., coronary, femoral, etc.) are exposed to cyclic flexure due to their tethering to surrounding tissue beds. It is believed that such stimuli result in a spatially variable biomechanical stress distribution, which has been implicated as a key modulator of remodeling associated with atherosclerotic lesion localization. In this study we utilized a combined ex vivo experimental/computational methodology to address the hypothesis that local variations in shear and mural stress associated with cyclic flexure influence the distribution of early markers of atherogenesis. Bilateral porcine femoral arteries were surgically harvested and perfused ex vivo under pulsatile arterial conditions. One of the paired vessels was exposed to cyclic flexure (0-0.7 cm(-1)) at 1 Hz for 12 h. During the last hour, the perfusate was supplemented with Evan's blue dye-labeled albumin. A custom tissue processing protocol was used to determine the spatial distribution of endothelial permeability, apoptosis, and proliferation. Finite element and computational fluid dynamics techniques were used to determine the mural and shear stress distributions, respectively, for each perfused segment. Biological data obtained experimentally and mechanical stress data estimated computationally were combined in an experiment-specific manner using multiple linear regression analyses. Arterial segments exposed to cyclic flexure had significant increases in intimal and medial apoptosis (3.42+/-1.02 fold, p=0.029) with concomitant increases in permeability (1.14+/-0.04 fold, p=0.026). Regression analyses revealed specific mural stress measures including circumferential stress at systole, and longitudinal pulse stress were quantitatively correlated with the distribution of permeability and apoptosis. The results demonstrated that local variation in mechanical stress in arterial segments subjected to cyclic flexure indeed influence the extent and spatial distribution of the early atherogenic markers. In addition, the importance of including mural stresses in the investigation of vascular mechanopathobiology was highlighted. Specific example results were used to describe a potential mechanism by which systemic risk factors can lead to a heterogeneous disease.

Twisted Blood Vessels: Symptoms, Etiology and Biomechanical Mechanisms

“…However, it is unclear how the tortuosity-induced flow and wall stress alterations affect the vascular cells and extracellular matrix and thus arterial wall remodeling. Previous studies have shown that the cyclic flexure of porcine femoral arteries affects extracellular matrix gene expression and cell proliferation [163,164] and is related to atherosclerosis [159]. Similarly, our laboratory recently observed nonsymmetric cell proliferation in buckled arteries [165].…”

Role of Tie1 in Shear Stress and Atherosclerosis

“…Cyclic stretch increases Tie1 expression in vitro in coronary endothelial cells (Zheng et al 2004), and in vivo at the aortic valve leaflet (Woo et al 2011). Arterial segments exposed to cyclic flexure are subjected to increased apoptosis and macromolecular permeability at the endothelium (Van Epps et al 2009). Thus, it will be beneficial to elucidate the response of Tie1 to the combined effects of stretch and shear stress as seen in aortic valve development and disease.…”

Development of a Semi-Automated, Bulk Seeding Device for Large Animal Model Implantation of Tissue Engineered Vascular Grafts

“…However, many bypass grafts in clinical practice must be bent and curved around obstructions. Future studies must demonstrate the grafts ability to withstand kinking in complex configurations in vivo (Van Epps et al, 2009) or the possibility to modify the scaffold structure in order to mitigate mechanical instability such as kinking or buckling.…”