Vascular Biology and Therapeutics Program, Yale School of Medicine, New Haven, Connecticut, USA; Department of Surgery, Yale School of Medicine, New Haven, Connecticut, USA.
Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut, USA.
J Thromb Haemost. 2024 Dec;22(12):3614-3628. doi: 10.1016/j.jtha.2024.07.028. Epub 2024 Aug 21.
Anticoagulation and antiplatelet therapy effectively inhibit neointimal hyperplasia (NIH) in both arterial and venous systems but not in arteriovenous fistulae (AVF). The main site of AVF failure is the juxta-anastomotic area that is characterized by disturbed flow compared with laminar flow in the arterial inflow and the venous outflow.
We hypothesized that early thrombus formation is required for eccentric and heterogeneous NIH in the presence of disturbed flow.
Needle puncture and sutured AVF were created in C57BL/6 mice, in PF4-Cre × mT/mG reporter mice, and in Wistar rats. Human AVF samples were second-stage basilic vein transpositions. The tissues were examined by histology, immunofluorescence, immunohistochemistry, and en face staining.
In the presence of disturbed flow, both mouse and human AVF showed eccentric and heterogeneous NIH. Maladapted vein wall was characterized by eccentric and heterogeneous neointima that was composed of a different abundance of thrombus and smooth muscle cells. PF4-cre × mT/mG reporter mice AVF showed that green fluorescent protein-labeled platelets deposit on the wall directly facing the fistula exit with endothelial cell loss and continue to accumulate in the presence of disturbed flow. Neither disturbed flow with limited endothelial cell loss nor nondisturbed flow induced heterogeneous neointima in different animal models.
Early thrombus contributes to late heterogeneous NIH in the presence of disturbed flow. Disturbed flow, large area of endothelial cell loss, and thrombus formation are critical to form eccentric and heterogeneous NIH. Categorization of adapted or maladapted walls may be helpful for therapy targeting heterogeneous NIH.
抗凝和抗血小板治疗能有效抑制动脉和静脉系统中的新生内膜增生（NIH），但不能抑制动静脉瘘（AVF）中的新生内膜增生。AVF 失效的主要部位是吻合口附近区域，其血流特点是与动脉流入和静脉流出的层流相比存在紊乱。
我们假设在血流紊乱的情况下，早期血栓形成是偏心性和异质性 NIH 的必要条件。
在 C57BL/6 小鼠、PF4-Cre×mT/mG 报告小鼠和 Wistar 大鼠中建立经皮穿刺和缝合的 AVF。人类 AVF 样本是二期头静脉转位。通过组织学、免疫荧光、免疫组化和全面染色来检查组织。
在血流紊乱的情况下，小鼠和人类的 AVF 均表现出偏心性和异质性的 NIH。适应性不良的静脉壁特征是偏心性和异质性的新生内膜，由不同数量的血栓和平滑肌细胞组成。PF4-Cre×mT/mG 报告小鼠的 AVF 显示，血小板在吻合口出口直接面对的壁上沉积，内皮细胞丢失，并在血流紊乱的情况下继续积累。无论是有限内皮细胞丢失的血流紊乱还是非血流紊乱，都不能在不同的动物模型中诱导异质性 NIH。
早期血栓形成有助于血流紊乱时晚期异质性 NIH 的形成。血流紊乱、大面积内皮细胞丢失和血栓形成对于形成偏心性和异质性 NIH 至关重要。适应性或非适应性壁的分类可能有助于针对异质性 NIH 的治疗。
