Journal of Biomechanics 34 (2001) 289–297 Role of tensile stress and strain in the induction of cell death in experimental vein grafts M.M. Moore a , J. Goldman a , A.R. Patel a , S. Chien b , S.Q. Liu a, * a Department of Biomedical Engineering, Northwestern University, 2145 Sheridan Road, Evanston, IL 60208-3107, USA b Department of Bioengineering, Whitaker Institute of Biomedical Engineering, University of California, San Diego, La Jolla, CA 92093-0427, USA Accepted 8 November 2000 Abstract Tensile stress and strain are known to induce vascular cell proliferation, a process that is physiologically counterbalanced by cell death. Here we investigate whether tensile stress and strain regulate vascular-cell death by using an end-to-end anastomosed rat vein graft model. In such a model, the circumferential tensile stress in the graft wall was increased by 140 times immediately after surgery compared with that in the venous wall. This change was associated with an increase in the percentage of TUNEL-positive cells at 1, 6, 24, 120, 240, and 720 h with two distinct peaks at 1 and 24 h (10.1  3.5 and 14.4  3.2%, respectively) compared with that in control jugular veins (0.4  0.5 and 0.5  0.5% at 1 and 24h, respectively). When tensile stress and strain in the vein graft wall were reduced by using a biomechanical engineering approach, the rate of cell death was reduced significantly (3.6  1.1 and 1.6  0.5% at 1 and 24 h, respectively). Furthermore, DEVD-CHO, a tetrapeptide aldehyde that inhibits the activity of caspase 3, significantly suppressed this event. These results suggest that a step increase in tensile stress and strain in experimental vein grafts induces rapid cell death, which is possibly mediated by cell death signaling mechanisms. # 2001 Elsevier Science Ltd. All rights reserved. Keywords: Apoptosis; SMC proliferation; Tissue engineering 1. Introduction Cell death, a process that occurs under the control of genetic programs or due to injury, has been shown to play a critical role in developmental morphogenesis and adaptive remodeling of biological systems (Chinnaiyan and Dixit, 1996; Haunstetter and Izumo, 1998; Jacobson et al., 1997; MacLellan and Schneider, 1997; Nagata, 1997). A variety of biological and chemical factors, including cell-death ligands and toxins, have been known to initiate and regulate cell death (Cho et al., 1997; Clutton, 1997; Haunstetter and Izumo, 1998; Hermann et al., 1997; Kaiser et al., 1997; MacLellan and Schneider, 1997; Nagata, 1997; Obeid et al., 1993; Spiegel et al., 1996). In the vascular system, cells are exposed not only to biological and chemical factors, but also to mechanical factors, including fluid-shear stress at the endothelial surface and tensile stress and strain in the wall of blood vessels. These mechanical factors have also been shown to influence vascular-cell death. However, the mechanisms remain unclear (Cheng et al., 1995; Dimmeler et al., 1996; Gobe et al., 1997; Hamet et al., 1996; Teiger et al., 1996). Previous investigations have demonstrated that a blood vessel is able to adapt to a change in tensile stress and strain in the wall of blood vessels. Hypertrophy of blood vessels and proliferation of smooth muscle cells are well-known examples of vascular adaptation to these mechanical factors (Fung, 1990; Liu and Fung, 1996; Liu, 1999a). Since cell death is a process that counter- balances cell proliferation (Haunstetter and Izumo, 1998; Jacobson et al., 1997; MacLellan and Schneider, 1997; Nagata, 1997; Oppenheim, 1991), cell death may also be involved in regulating mechanically induced vascular remodeling. In a recent study, Mayr and colleagues demonstrated that cell apoptosis was induced in a mouse vein-to- artery graft model, but not in a vein-to-vein graft model (Mayr et al., 2000). We have also found using a rat vein graft model that tensile stress, which was 140 times higher in the graft wall than that in the venous wall during the initial period (Liu and Fung, 1998), was associated with a rapid decrease in cell density and SMC *Corresponding author. Tel.: +847-491-2946; fax: +847-491-4928. E-mail address: sliu@northwestern.edu (S.Q. Liu). 0021-9290/01/$ - see front matter # 2001 Elsevier Science Ltd. All rights reserved. PII:S0021-9290(00)00217-7