Postdoctoral researcher University of Texas Health Science Center, Houston, McGovern Medical School Houston, Texas, United States
Disclosure(s):
Jiaying Zheng, PhD: No financial relationships to disclose
Introduction/Rationale: Microglia are the resident immune cells of the central nervous system, classically studied for neuroinflammation. A specialized subset, vessel-associated microglia (VAM), whose somata directly contact capillaries, constitutes ~30% of microglia in the naïve brain. Only recently have VAM been recognized as regulators of brain circulation, influencing blood–brain barrier (BBB) integrity and cerebral blood flow, yet their role in pathological vascular remodeling remains unclear. To address this gap, we used glioma models in which peritumoral capillaries undergo extensive vascular remodeling and BBB dysfunction, providing an in vivo platform to probe capillary vulnerability and vascular stability.
Methods: We combined pharmacological microglial ablation via CSF1R inhibitors with longitudinal in vivo two-photon imaging to visualize microglia–capillary interactions. Behavioral testing, survival analysis, T2-weighted MRI, and immunostaining were performed in parallel.
Results: Over half of the microglia-depleted mice developed acute, lethal paralysis by 15 days, whereas control tumor-bearing mice remained asymptomatic and survived 30 days. MRI revealed large intracranial hemorrhages and severe edema, and two-photon imaging showed nodular, abnormal vasculature at paralysis onset. The peritumoral region contained dense capillary networks with a marked increase in VAMs (>60%). Genetic lineage tracing confirmed these cells were microglia, exhibiting elongated, vessel-wrapping morphology, also observed following single-vessel photothrombosis and consistent with a response to capillary injury.
Conclusion: Our findings identify VAMs as critical neurovascular stabilizers that preserve peritumoral capillary integrity and prevent lethal hemorrhage in glioma, highlighting an essential immune role in brain vascular homeostasis. Notably, intracranial hemorrhage has repeatedly emerged across clinical trials of CSF1R inhibitors, raising important safety considerations for CSF1R-targeted therapies in the diseased brain.
