Intravitreal anti-vascular endothelial growth factor (VEGF) drugs have revolutionized the treatment of neovascular age-related macular degeneration (NVAMD). However, many patients suffer from incomplete response to anti-VEGF therapy (IRT), which is defined as (1) persistent (plasma) fluid exudation; (2) unresolved or new hemorrhage; (3) progressive lesion fibrosis; and/or (4) suboptimal vision recovery. The first three of these collectively comprise the problem of persistent disease activity (PDA) in spite of anti-VEGF therapy. Meanwhile, the problem of suboptimal vision recovery (SVR) is defined as a failure to achieve excellent functional visual acuity of 20/40 or better in spite of sufficient anti-VEGF treatment. Thus, incomplete response to anti-VEGF therapy, and specifically PDA and SVR, represent significant clinical unmet needs.

In this review, we will explore PDA and SVR in NVAMD, characterizing the clinical manifestations and exploring the pathobiology of each. We will demonstrate that PDA occurs most frequently in NVAMD patients who develop high-flow CNV lesions with arteriolarization, in contrast to patients with capillary CNV who are highly responsive to anti-VEGF therapy. We will review investigations of experimental CNV and demonstrate that both types of CNV can be modeled in mice. We will present and consider a provocative hypothesis: formation of arteriolar CNV occurs via a distinct pathobiology, termed neovascular remodeling (NVR), wherein blood-derived macrophages infiltrate the incipient CNV lesion, recruit bone marrow-derived mesenchymal precursor cells (MPCs) from the circulation, and activate MPCs to become vascular smooth muscle cells (VSMCs) and myofibroblasts, driving the development of high-flow CNV with arteriolarization and perivascular fibrosis. In considering SVR, we will discuss the concept that limited or poor vision in spite of anti-VEGF may not be caused simply by photoreceptor degeneration but instead may be associated with photoreceptor synaptic dysfunction in the neurosensory retina overlying CNV, triggered by infiltrating blood-derived macrophages and mediated by Müller cell activation Finally, for each of PDA and SVR, we will discuss current approaches to disease management and treatment and consider novel avenues for potential future therapies.

玻璃体内抗血管内皮生长因子（VEGF）药物彻底改变了新生血管性年龄相关性黄斑变性（NVAMD）的治疗。然而，许多患者对抗VEGF治疗（IRT）反应不完全，其定义为（1）持续性（血浆）液体渗出；(2) 未消退或新发生的出血；(3)病灶进行性纤维化；和/或 (4) 视力恢复不佳。尽管进行了抗 VEGF 治疗，前三个问题共同构成了疾病活动持续 (PDA) 的问题。同时，次优视力恢复（SVR）问题被定义为尽管进行了充分的抗VEGF治疗，但仍无法实现20/40或更好的优异功能性视力。因此，抗 VEGF 治疗，特别是 PDA 和 SVR 的不完全反应代表了重大的临床未满足需求。

在这篇综述中，我们将探讨 NVAMD 中的 PDA 和 SVR，描述其临床表现并探讨各自的病理学。我们将证明，PDA 最常发生在因动脉化而发生高流量 CNV 病变的 NVAMD 患者中，而患有毛细血管 CNV 的患者对抗 VEGF 治疗高度敏感。我们将回顾实验性 CNV 的研究，并证明这两种类型的 CNV 都可以在小鼠中建模。我们将提出并考虑一个令人兴奋的假设：小动脉 CNV 的形成是通过一种独特的病理学发生的，称为新生血管重塑 (NVR)，其中血液来源的巨噬细胞浸润早期的 CNV 病变，从血管中招募骨髓来源的间充质前体细胞 (MPC)。循环，并激活 MPC 成为血管平滑肌细胞 (VSMC) 和肌成纤维细胞，驱动高流量 CNV 的发展，伴有动脉化和血管周围纤维化。在考虑 SVR 时，我们将讨论这样一个概念：尽管使用了抗 VEGF 药物，视力仍有限或较差，这可能不是简单地由光感受器变性引起的，而是可能与覆盖 CNV 的神经感觉视网膜中的光感受器突触功能障碍有关，这是由血源性浸润触发的。最后，对于 PDA 和 SVR，我们将讨论当前的疾病管理和治疗方法，并考虑未来潜在治疗的新途径。