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<p>Capillary-Associated Microglia (CAMs) are increasingly recognized as integral components of the neurovascular unit (NVU) that interface with intracerebral capillaries and are implicated in microcirculatory regulation, neurovascular coupling (NVC), and blood–brain barrier (BBB) maintenance. Rather than a rigid lineage-defined subset, CAMs are often best conceptualized as an anatomically anchored and context-responsive microglial state in which somata and/or primary processes closely appose the capillary wall, enabling continuous sensing of vascular-derived signals and local modulation of vascular function. Advances in in vivo two-photon imaging, single-cell and spatial transcriptomics, and genetic perturbation approaches have begun to delineate their positioning dynamics and candidate molecular programs. Mechanistically, CAMs can engage purinergic signaling—most prominently via the PANX1–P2Y12R axis—to detect extracellular nucleotides and support process responses and capillary association, while additional pathways involving COX-1–dependent prostanoid production and CD39-mediated nucleotide hydrolysis may contribute to basal tone regulation and activity-dependent vascular reactivity, in part through local adenosine availability. Through coordinated interactions with endothelial cells, pericytes, astrocytes, and neurons, CAMs occupy a strategic immunovascular interface, where they may couple immune surveillance to BBB integrity and metabolic homeostasis. In disease, alterations in the positioning and signaling of CAMs have been linked to a range of neurological and neurovascular disorders, including Alzheimer’s and Parkinson’s diseases, cerebral small vessel disease, diabetic encephalopathy, and ischemic stroke, with emerging evidence suggesting that chronic inflammatory or metabolic stress can reshape these programs and compromise NVC. Key challenges remain in establishing operational definitions and cross-species comparability, achieving long-term in vivo tracking with causal resolution, and improving the physiological fidelity of in vitro models. Future work will benefit from standardized criteria for CAMs identification, longitudinal multimodal imaging integrated with spatial omics, refined microphysiological platforms, and targeted modulation or delivery strategies, with the aim of translating mechanistic insights into reliable biomarkers and therapeutic opportunities for neuroinflammatory and neurovascular pathologies.</p>

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Capillary-Associated Microglia in Neurovascular Coupling: Localization, Mechanisms, and Disease Implications

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年2月11日

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  • Haofan Lu,
  • Yonggang Zhang,
  • Cheng Chen,
  • Hairou Xie,
  • Yuntao Li,
  • Sheng Qiu

摘要

Capillary-Associated Microglia (CAMs) are increasingly recognized as integral components of the neurovascular unit (NVU) that interface with intracerebral capillaries and are implicated in microcirculatory regulation, neurovascular coupling (NVC), and blood–brain barrier (BBB) maintenance. Rather than a rigid lineage-defined subset, CAMs are often best conceptualized as an anatomically anchored and context-responsive microglial state in which somata and/or primary processes closely appose the capillary wall, enabling continuous sensing of vascular-derived signals and local modulation of vascular function. Advances in in vivo two-photon imaging, single-cell and spatial transcriptomics, and genetic perturbation approaches have begun to delineate their positioning dynamics and candidate molecular programs. Mechanistically, CAMs can engage purinergic signaling—most prominently via the PANX1–P2Y12R axis—to detect extracellular nucleotides and support process responses and capillary association, while additional pathways involving COX-1–dependent prostanoid production and CD39-mediated nucleotide hydrolysis may contribute to basal tone regulation and activity-dependent vascular reactivity, in part through local adenosine availability. Through coordinated interactions with endothelial cells, pericytes, astrocytes, and neurons, CAMs occupy a strategic immunovascular interface, where they may couple immune surveillance to BBB integrity and metabolic homeostasis. In disease, alterations in the positioning and signaling of CAMs have been linked to a range of neurological and neurovascular disorders, including Alzheimer’s and Parkinson’s diseases, cerebral small vessel disease, diabetic encephalopathy, and ischemic stroke, with emerging evidence suggesting that chronic inflammatory or metabolic stress can reshape these programs and compromise NVC. Key challenges remain in establishing operational definitions and cross-species comparability, achieving long-term in vivo tracking with causal resolution, and improving the physiological fidelity of in vitro models. Future work will benefit from standardized criteria for CAMs identification, longitudinal multimodal imaging integrated with spatial omics, refined microphysiological platforms, and targeted modulation or delivery strategies, with the aim of translating mechanistic insights into reliable biomarkers and therapeutic opportunities for neuroinflammatory and neurovascular pathologies.