Tortuous arteries are often associated with aging, hypertension, atherosclerosis, and degenerative vascular diseases, but the mechanisms are poorly understood. Our recent theoretical analysis suggested that mechanical instability (buckling) may lead to tortuous blood vessels. The objectives of this study were to determine the critical pressure of artery buckling and the effects of elastin degradation and surrounding matrix support on the mechanical stability of arteries. The mechanical properties and critical buckling pressures, at which arteries become unstable and deform into tortuous shapes, were determined for a group of five normal arteries using pressurized inflation and buckling tests. Another group of nine porcine arteries were treated with elastase (8 U/ml), and the mechanical stiffness and critical pressure were obtained before and after treatment. The effect of surrounding tissue support was simulated using a gelatin gel. The critical pressures of the five normal arteries were 9.52 kPa (SD 1.53) and 17.10 kPa (SD 5.11) at axial stretch ratios of 1.3 and 1.5, respectively, while model predicted critical pressures were 10.11 kPa (SD 3.12) and 17.86 kPa (SD 5.21), respectively. Elastase treatment significantly reduced the critical buckling pressure (P < 0.01). Arteries with surrounding matrix support buckled into multiple waves at a higher critical pressure. We concluded that artery buckling under luminal pressure can be predicted by a buckling equation. Elastin degradation weakens the arterial wall and reduces the critical pressure, which thus leads to tortuous vessels. These results shed light on the mechanisms of the development of tortuous vessels due to elastin deficiency.

Stenosis is a critical problem in the long-term efficacy of tissue-engineered vascular grafts (TEVGs). We previously showed that host monocyte infiltration and activation within the graft drives stenosis and that TGF-b receptor 1 (TGF-bR1) inhibition can prevent it, but the latter effect was attributed primarily to inhibition of mesenchymal cell expansion. In this study, we assessed the effects of TGF-bR1 inhibition on the host monocytes. Biodegradable TEVGs were implanted as inferior vena cava interposition conduits in 2 groups of C57BL/6 mice (n = 25/group): unseeded grafts and unseeded grafts with TGF-bR1 inhibitor systemic treatment for the first 2 wk. The TGF-bR1 inhibitor treatment effectively improved TEVG patency at 6 mo compared to the untreated control group (91.7 vs. 48%, P < 0.001), which is associated with a reduction in classic activation of mononuclear phagocytes. Consistent with these findings, the addition of rTGF-b to LPS/IFN-g-stimulated monocytes enhanced secretion of inflammatory cytokines TNF-a, IL-12, and IL-6; this effect was blocked by TGF-bR1 inhibition (P < 0.0001). These findings suggest that the TGF-b signaling pathway contributes to TEVG stenosis by inducing classic activation of host monocytes. Furthermore, blocking monocyte activation by TGF-bR1 inhibition provides a viable strategy for preventing TEVG stenosis while maintaining neotissue formation.-Lee, Y.-U., de Dios Ruiz-Rosado, J., Mahler, N., Best, C. A., Tara, S., Yi, T., Shoji, T., Sugiura, T., Lee, A. Y., Robledo-Avila, F., Hibino, N., Pober, J. S., Shinoka, T., Partida-Sanchez, S., Breuer, C. K. TGF-b receptor 1 inhibition prevents stenosis of tissue-engineered vascular grafts by reducing host mononuclear phagocyte activation. FASEB J. 30, 2627FASEB J. 30, -2636FASEB J. 30, (2016. www.fasebj.orgPrevious data from our laboratory demonstrated that bone marrow-derived mononuclear cell (BM-MNC) seeding of tissue-engineered vascular grafts (TEVGs) promoted the process of neovessel formation (1). In contrast to our original expectation that the seeded cells differentiated into mature vascular cells, we found that the seeded BMMNCs disappeared within a few days of implantation. Instead, the seeded cells exerted their effect by controlling recruitment of host mononuclear phagocytes in early time point, which recruit smooth muscle cells and endothelial cells (;3 wk) (1). While BM-MNC seeding also significantly improved patency of the TEVGs, both in a clinical study and in mouse models, the occurrence of graft stenosis remained a major complication in 25% of TEVG recipients (2, 3). Our mouse models revealed that the formation of TEVG stenosis is also driven by paracrine functions of infiltrating host mononuclear phagocytes. A significant proportion of cells that form stenotic lesions in the mouse model appear to arise from the endothelialmesenchymal transition (Endo-MT) (1,3,4). Because TGFb signaling is the key to multiple vascular disorders, including Endo-MT (5-8), we investigated if inhibition of this cytokine coul...

Tortuous arteries associated with aneurysms have been observed in aged patients with atherosclerosis and hypertension. However, the underlying mechanism is poorly understood. The objective of this study was to determine the effect of aneurysms on arterial buckling instability and the effect of buckling on aneurysm wall stress. We investigated the mechanical buckling and post-buckling behavior of normal and aneurysmal carotid arteries and aorta’s using computational simulations and experimental measurements to elucidate the interrelationship between artery buckling and aneurysms. Buckling tests were done in porcine carotid arteries with small aneurysms created using elastase treatment. Parametric studies were done for model aneurysms with orthotropic nonlinear elastic walls using finite element simulations. Our results demonstrated that arteries buckled at a critical buckling pressure and the post-buckling deflection increased nonlinearly with increasing pressure. The presence of an aneurysm can reduce the critical buckling pressure of arteries, although the effect depends on the aneurysm’s dimensions. Buckled aneurysms demonstrated a higher peak wall stress compared to unbuckled aneurysms under the same lumen pressure. We conclude that aneurysmal arteries are vulnerable to mechanical buckling and mechanical buckling could lead to high stresses in the aneurysm wall. Buckling could be a possible mechanism for the development of tortuous aneurysmal arteries such as in the Loeys-Dietz syndrome.

Arteries often demonstrate geometric variations such as elliptic and eccentric cross sections, stenosis, and tapering along the longitudinal axis. Effects of these variations on the mechanical stability of the arterial wall have not been investigated. The objective of this study was to determine the buckling behavior of arteries with elliptic, eccentric, stenotic, and tapered cross sections. The arterial wall was modeled as a homogenous anisotropic nonlinear material. Finite element analysis was used to simulate the buckling process of these arteries under lumen pressure and axial stretch. Our results demonstrated that arteries with an oval cross section buckled in the short axis direction at lower critical pressures compared to circular arteries. Eccentric cross-sections, stenosis, and tapering also decreased the critical pressure. Stenosis led to dramatic pressure variations along the vessel and reduced the buckling pressure. In addition, tapering shifted the buckling deformation profile of the artery towards the distal end. We conclude that geometric variations reduce the critical pressure of arteries and thus make the arteries more prone to mechanical instability than circular cylindrical arteries. These results improve our understanding of the mechanical behavior of arteries.

Aim We investigated the effect of cell seeding dose and incubation time on tissue-engineered vascular graft (TEVG) patency. Materials & methods Various doses of bone marrow-derived mononuclear cells (BM-MNCs) were seeded onto TEVGs, incubated for 0 or 12 h, and implanted in C57BL/6 mice. Different doses of human BM-MNCs were seeded onto TEVGs and measured for cell attachment. Results The incubation time showed no significant effect on TEVG patency. However, TEVG patency was significantly increased in a dose-dependent manner. In the human graft, more bone marrow used for seeding resulted in increased cell attachment in a dose-dependent manner. Conclusion Increasing the BM-MNC dose and reducing incubation time is a viable strategy for improving the performance and utility of the graft.