Reperfusion reshapes the temporal evolution of neurovascular injury after ischemic stroke

Reperfusion is the cornerstone of acute ischemic stroke treatment, yet how it reshapes the temporal trajectory of neurovascular injury beyond the acute phase remains unclear. Here, we developed permanent (pStroke) and transient (tStroke) cortical ischemia mouse models compatible with longitudinal in vivo two-photon imaging to investigate the evolution of neurovascular injury following ischemia and reperfusion. Although reperfusion markedly reduced acute infarct development and neuronal loss, it failed to restore neurovascular homeostasis. Longitudinal two-photon imaging of ischemic mice revealed neuronal hyperexcitability and aberrant network synchronization, concomitant with impaired vascular remodeling and sustained vascular leakage following reperfusion. Histological analyses further demonstrated progressive neurodegeneration, chronic microglial activation and persistent alterations in the neurovascular unit despite improved preservation of brain tissue during the acute phase. Analysis of dextran permeability revealed size-selective BBB dysfunction, indicating that reperfusion induces prolonged impairment of vascular barrier properties rather than complete vascular recovery. Together, our findings demonstrate that reperfusion might reshape the temporal evolution of ischemic brain injury by limiting acute tissue damage while also promoting chronic neurovascular dysfunction, identifying persistent vascular instability as a potential therapeutic target for improving long-term recovery after ischemic stroke.