Zika virus (ZIKV) infection has been linked to vascular complications, yet the basis of vascular injury after apparent clearance of circulating virus remains poorly understood. This study examined the temporal progression of ZIKV-associated vascular damage and defined the contribution of non-structural protein 3 (NS3) to oxidative stress-mediated vascular dysfunction. ZIKV infection was modeled in interferon-α/β receptor-deficient A129 mice and immunocompetent northern pig-tailed macaques ( Macaca leonina). Vascular pathology and function were evaluated using histopathology, transmission electron microscopy, immunofluorescence, and vascular reactivity assays, and primary murine vascular smooth muscle cells were used for mechanistic analyses. Transcriptomic profiling, antioxidant pathway assessment, and co-immunoprecipitation assays were performed to identify NS3-dependent molecular events. In A129 mice, ZIKV remained detectable in blood and induced progressive vascular injury. In contrast, in immunocompetent M. leonina, circulating viral RNA declined to undetectable levels by 15 days post-infection (dpi); however, viral RNA and envelope protein remained detectable in vascular tissues at 63 dpi, indicating sustained vascular viral retention after blood clearance. Across both models, ZIKV infection caused sustained endothelial injury, increased migration of vascular smooth muscle cells, and impaired vascular contractile responses. Mechanistically, NS3 interacted with nuclear factor erythroid 2-related factor 2 (Nrf2), restricted Nrf2 nuclear translocation, and disrupted the Nrf2/Kelch-like ECH-associated protein 1/glutathione peroxidase 4 (Nrf2/KEAP1/GPX4) antioxidant signaling pathway, thereby increasing oxidative stress. Restoration of Nrf2 activity significantly improved antioxidant capacity and attenuated vascular injury. These findings indicate that vascular viral persistence may contribute to post-viremic vascular dysfunction and identify NS3-mediated suppression of Nrf2 signaling as a mechanism underlying ZIKV-induced vascular injury. 寨卡病毒（Zika virus, ZIKV）感染与血管并发症相关，但其导致血管损伤的机制，尤其是病毒从血液中清除后是否仍可引起持续性血管损伤及其相关机制，尚未阐明。本文中我们对 ZIKV 感染过程中病毒清除前后血管结构与功能损伤的变化进行了系统研究，并探讨了 ZIKV 非结构蛋白3（non-structural protein 3, NS3）在氧化应激介导的血管功能障碍中的作用。该研究分别在Ⅰ型干扰素受体缺陷的 A129 小鼠和免疫功能正常的非人灵长类北平顶猴（ Macaca leonina）中建立 ZIKV 感染及血管损伤模型。采用组织病理学、透射电镜、免疫荧光及血管反应性实验评价血管结构与功能变化，并以小鼠原代血管平滑肌细胞（murine vascular smooth muscle cells, mVSMCs）开展机制研究。通过转录组分析、抗氧化通路评价及免疫共沉淀（co-immunoprecipitation, Co-IP）实验，阐明 NS3 相关的分子机制。结果显示，在 A129 小鼠中，ZIKV 可持续存在于血液中并导致持续性血管损伤。相比之下，在免疫功能正常的北平顶猴中，血液中的病毒 RNA 于感染后15天（days post-infection, DPI）降至检测限以下；然而，在 63 DPI 时，血管组织中仍可检测到病毒 RNA 和包膜蛋白，提示ZIKV成分可持续滞留于血管组织中。在两种模型中，ZIKV 感染均可导致持续性血管内皮损伤、促进VSMCs迁移，并损害血管反应性。机制研究表明，NS3 与核因子 E2 相关因子2（nuclear factor erythroid 2-related factor 2, Nrf2）相互作用，抑制其核转位，并抑制 Nrf2/Kelch 样 ECH 相关蛋白1（Kelch-like ECH-associated protein 1, KEAP1）/谷胱甘肽过氧化物酶4（glutathione peroxidase 4, GPX4）抗氧化信号通路，进而增强氧化应激。恢复 Nrf2 活性可显著提高细胞抗氧化能力并减轻血管损伤。ZIKV 感染不仅可在病毒血症阶段引起血管损伤，在血液中病毒清除后仍可能通过病毒成分在血管组织中的持续滞留导致持续性血管损伤。NS3 介导的 Nrf2 抗氧化防御抑制可能是 ZIKV 诱导血管氧化损伤的重要机制。.