JVS - Vascular Science (Jan 2020)
Imatinib attenuates neotissue formation during vascular remodeling in an arterial bioresorbable vascular graft
Abstract
Background: Bioresorbable vascular grafts (BVGs) can transform biologically into active blood vessels and represent an alternative to traditional synthetic conduits, which are prone to complications such as infection and thrombosis. Although platelet-derived growth factors and c-Kit positive cells play an important role in smooth muscle cell (SMC) migration and proliferation in vascular injury, atherosclerosis, or allograft, their roles in the vascular remodeling process of an arterial BVG remains unknown. Thus, we assessed the neottisue formation on arterial BVG remodeling by administrating imatinib, which is both a platelet-derived growth factor receptor kinase inhibitor and c-Kit receptor kinase inhibitor, in a murine model. Methods: BVGs were composed of an inner poly(L-lactic-co-ε-caprolactone) copolymer sponge layer and an outer electrospun poly(L-lactic acid) nanofiber layer, which were implanted into the infrarenal abdominal aortas of C57BL/6 mice. After graft implantation, saline or 100 mg/kg of imatinib was administrated intraperitoneally daily for 2 weeks (n = 20 per group). Five mice in each group were scheduled to be humanely killed at 3 weeks and 15 at 8 weeks, and BVGs were explanted for histologic assessments. Results: Graft patency during the 8-week observational period was not significantly different between groups (control, 86.7% vs imatinib, 80.0%; P > .999). Neotissue formation consisting of endothelialization, smooth muscle proliferation, and deposition of collagen and elastin was not observed in either group at 3 weeks. Similar endothelialization was achieved in both groups at 8 weeks, but thickness and percent area of neotissue formation were significantly higher in the control group than in the imatinib group, (thickness, 30.1 ± 7.2 μm vs 19.6 ± 4.5 μm [P = .001]; percent area, 9.8 ± 2.7% vs 6.8 ± 1.8% [P = .005]). Furthermore, SMC layer and deposition of collagen and elastin were better organized at 8 weeks in the control group compared with the imatinib group. The thickness of SMC layer and collagen fiber area were significantly greater at 8 weeks in the control group than in the imatinib group (P < .001 and P = .026, respectively). Because there was no difference in the inner diameter of explanted BVGs (831.7 ± 63.4 μm vs 841.8 ± 41.9 μm; P = .689), neotissue formation was thought to advance toward the outer portion of the BVG with degradation of the polymer scaffold. Conclusions: Imatinib attenuates neotissue formation during vascular remodeling in arterial bioresorbable vascular grafts (BVGs) by inhibiting SMC layer formation and extracellular matrix deposition. : Clinical Relevance: This study demonstrated that imatinib attenuated neotissue formation during vascular remodeling in arterial Bioresorbable vascular graft (BVG) by inhibiting smooth muscle cell formation and extracellular matrix deposition. In addition, as imatinib did not modify the inner diameter of BVG, neotissue advanced circumferentially toward the outer portion of the neovessel. Currently, BVGs have not yet been clinically applied to the arterial circulation. The results of this study are helpful for the design of BVG that can achieve an optimal balance between polymer degradation and neotissue formation.
