Cells. 2026 Jul 24. pii: 1322. [Epub ahead of print]15(15):
Ischemic stroke remains a leading cause of death and long-term disability worldwide. Although acute reperfusion therapies have improved outcomes in selected patients, effective strategies that directly promote neurovascular repair during the subacute and chronic phases remain limited. Vascular network remodeling in the peri-infarct region is increasingly recognized as a key process supporting tissue repair, blood-brain barrier restoration, and functional recovery after stroke. Microglia, as resident immune cells of the central nervous system, undergo dynamic morphological, metabolic, and functional changes after ischemic injury and participate in inflammation, phagocytic clearance, blood-brain barrier regulation, and tissue repair. Among repair-associated microglial states, microglia with M2d-like features have attracted increasing attention because of their potential association with immunoregulation and pro-vascular repair. However, whether repair-associated microglia with M2d-like features represent a distinct and stable microglial subtype after stroke remains unresolved. In this review, we summarize current evidence linking repair-associated microglial responses to vascular network remodeling after ischemic stroke, with particular emphasis on the conceptual value of the M2d-like state. We discuss putative mechanisms involving paracrine signaling, perivascular localization, metabolic reprogramming, and extracellular vesicle-mediated communication. We also evaluate therapeutic implications, including traditional Chinese medicine, extracellular vesicle-based strategies, and nanodelivery systems. However, current therapeutic evidence does not establish that these interventions specifically induce M2d-like microglial states. We highlight the need for rigorous validation of cellular identity, spatial localization, and functional vascular outcomes. Overall, the M2d-like framework provides a candidate perspective for understanding immune-vascular coupling after stroke, but further studies integrating single-cell omics, spatial mapping, lineage tracing, and functional vascular assessment are required to define the identity and functional contribution of repair-associated microglia with M2d-like features. Method: This article is a narrative review. The relevant literature was searched in PubMed from database inception to June 2026 using combinations of the terms "ischemic stroke," "microglia," "macrophage," "vascular remodeling," "angiogenesis," "M2d," "extracellular vesicles," "traditional Chinese medicine," and "nanomedicine." Priority was given to original studies directly examining microglial or myeloid responses and vascular repair after ischemic stroke. Relevant review articles were included to provide conceptual background. Because direct evidence for M2d-like microglial responses after stroke remains limited, selected studies involving peripheral macrophages, tumor-associated macrophages, traditional Chinese medicine, extracellular vesicles, and nanomedicine were included as indirect or hypothesis-generating evidence. Evidence was interpreted according to the disease model, cellular source, and vascular outcomes examined, with stroke-specific microglial studies regarded as more directly relevant than evidence extrapolated from non-stroke or non-microglial models.
Keywords: M2d-like features; angiogenesis; blood–brain barrier; extracellular vesicles; ischemic stroke; neurovascular unit; repair-associated microglia; traditional Chinese medicine; vascular network remodeling