Imatinib attenuates neotissue formation during vascular remodeling in an arterial bioresorbable vascular graft.
Imatinib attenuates neotissue formation during vascular remodeling in an arterial bioresorbable vascular graft.
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DOI：
10.1016/j.jvssci.2020.03.002
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发表时间：
2020
期刊：
影响因子：
--
通讯作者：
Shinoka T
中科院分区：
文献类型：
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作者：
Miyachi H;Tara S;Otsuru S;Yi T;Lee YU;Drews JD;Nakayama H;Miyamoto S;Sugiura T;Shoji T;Breuer CK;Shinoka T
生物可吸收血管移植物（BVG）可以通过生物学方式转化为活性血管，是传统合成导管的替代品，传统合成导管容易出现感染和血栓形成等并发症。尽管血小板源性生长因子和 c-Kit 阳性细胞在血管损伤、动脉粥样硬化或同种异体移植中的平滑肌细胞 (SMC) 迁移和增殖中发挥重要作用，但它们在动脉 BVG 血管重塑过程中的作用仍不清楚。因此，我们通过在小鼠模型中给予伊马替尼（一种血小板衍生生长因子受体激酶抑制剂和 c-Kit 受体激酶抑制剂）来评估动脉 BVG 重塑中的新组织形成。 BVG由内部聚（L-乳酸-共聚-ε-己内酯）共聚物海绵层和外部电纺聚（L-乳酸）纳米纤维层组成，被植入C57BL/6小鼠的肾下腹主动脉中。移植物植入后，每天腹腔注射生理盐水或 100 mg/kg 伊马替尼，持续 2 周（每组 n = 20）。每组中的 5 只小鼠计划在 3 周时被人道处死，15 只小鼠在 8 周时被人道处死，并取出 BVG 进行组织学评估。 8 周观察期内的移植物通畅率在各组之间没有显着差异（对照组为 86.7%，伊马替尼为 80.0%；P > .999）。 3 周后，两组均未观察到由内皮化、平滑肌增殖以及胶原蛋白和弹性蛋白沉积组成的新组织形成。 8 周时，两组均实现了类似的内皮化，但对照组的厚度和新组织形成面积百分比显着高于伊马替尼组（厚度，30.1 ± 7.2 μm vs 19.6 ± 4.5 μm [P = .001]；面积百分比，9.8 ± 2.7% vs 6.8 ± 1.8%） [P=.005]）。此外，与伊马替尼组相比，对照组的 SMC 层以及胶原蛋白和弹性蛋白的沉积在第 8 周时组织得更好。 8 周时，对照组的 SMC 层厚度和胶原纤维面积显着大于伊马替尼组（分别为 P < .001 和 P = .026）。由于外植 BVG 的内径没有差异（831.7 ± 63.4 μm 与 841.8 ± 41.9 μm；P = .689），因此认为新组织形成随着聚合物支架的降解而向 BVG 的外部推进。伊马替尼通过抑制 SMC 层形成和细胞外基质沉积，减弱动脉生物可吸收血管移植物 (BVG) 血管重塑过程中的新组织形成。这项研究表明，伊马替尼通过抑制平滑肌细胞形成和细胞外基质沉积，减弱动脉生物可吸收血管移植物（BVG）血管重塑过程中的新组织形成。此外，由于伊马替尼没有改变 BVG 的内径，因此新组织沿圆周向新血管的外部推进。目前，BVG尚未应用于动脉循环临床。这项研究的结果有助于BVG的设计，使其能够在聚合物降解和新组织形成之间实现最佳平衡。
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. 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. 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. Imatinib attenuates neotissue formation during vascular remodeling in arterial bioresorbable vascular grafts (BVGs) by inhibiting SMC layer formation and extracellular matrix deposition. 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.