Key Laboratory for Biomechanics and Mechanobiology (Beihang University) of Ministry of Education, Beijing Advanced Innovation Center for Biomedical Engineering, School of Biological Science and Medical Engineering, Beihang University, Beijing, 100083, PR China.
School of Pharmacy, Changzhou University, Changzhou, 213164, PR China.
Biomaterials. 2025 Mar;314:122877. doi: 10.1016/j.biomaterials.2024.122877. Epub 2024 Oct 5.
Endothelial cell (EC) dysfunction within the aorta has long been recognized as a prominent contributor to the progression of atherosclerosis and the subsequent failure of vascular graft transplantation. However, the direct relationship between EC dysfunction and vascular remodeling remains to be investigated. In this study, we sought to address this knowledge gap by employing a strategy involving the release of glutamine synthetase (GS), which effectively activated endothelial metabolism and mitigates EC dysfunction. To achieve this, we developed GS-loaded small-diameter vascular grafts (GSVG) through the electrospinning technique, utilizing dual-component solutions consisting of photo-crosslinkable hyaluronic acid and polycaprolactone. Through an in vitro model of oxidized low-density lipoprotein-induced injury in human umbilical vein endothelial cells (HUVECs), we provided compelling evidence that the GSVG promoted the restoration of motility, angiogenic sprouting, and proliferation in dysfunctional HUVECs by enhancing cellular metabolism. Furthermore, the sequencing results indicated that these effects were mediated by miR-122-5p-related signaling pathways. Remarkably, the GSVG also exhibited regulatory capabilities in shifting vascular smooth muscle cells towards a contractile phenotype, mitigating inflammatory responses and thereby preventing vascular calcification. Finally, our data demonstrated that GS incorporation significantly enhanced re-endothelialization of vascular grafts in a ferric chloride-injured rat model. Collectively, our results offer insights into the promotion of re-endothelialization in vascular grafts by restoring dysfunctional ECs through the augmentation of cellular metabolism.
主动脉内皮细胞（EC）功能障碍一直被认为是动脉粥样硬化进展和随后血管移植物移植失败的主要原因。然而，EC 功能障碍与血管重构之间的直接关系仍有待研究。在这项研究中，我们通过释放谷氨酰胺合成酶（GS）的策略来解决这一知识空白，该策略有效地激活了内皮代谢并减轻了 EC 功能障碍。为了实现这一目标，我们通过静电纺丝技术开发了载有 GS 的小直径血管移植物（GSVG），使用由可光交联透明质酸和聚己内酯组成的双组分溶液。通过人脐静脉内皮细胞（HUVEC）氧化型低密度脂蛋白诱导损伤的体外模型，我们提供了有力的证据表明，GSVG 通过增强细胞代谢，促进功能失调的 HUVEC 中运动、血管生成发芽和增殖的恢复。此外，测序结果表明，这些作用是通过 miR-122-5p 相关信号通路介导的。值得注意的是，GSVG 还具有调节血管平滑肌细胞向收缩表型转变的能力，减轻炎症反应，从而防止血管钙化。最后，我们的数据表明，GS 的掺入显著增强了氯化铁损伤大鼠模型中血管移植物的再内皮化。总之，我们的结果提供了通过增强细胞代谢来促进血管移植物中功能失调的 EC 再内皮化的见解。
