Venular-centered thrombo-inflammation drives microvascular failure after arterial recanalization in acute mesenteric ischemia: a translational study

Abstract

Acute mesenteric ischemia (AMI) remains associated with high mortality despite prompt revascularization, suggesting that downstream ischemia-reperfusion injury contributes to poor outcomes. However, the microvascular mechanisms underlying this process remain poorly defined. We analyzed admission blood samples from patients with arterial AMI and non-ischemic controls and investigated thrombo-inflammatory responses in a murine superior mesenteric artery occlusion (SMAO) model. In mice, intravital microscopy was used to directly visualize mesenteric microcirculatory flow and thrombo-inflammatory events during ischemia-reperfusion. Patients with AMI displayed a marked systemic thrombo-inflammatory profile, characterized by elevated inflammatory markers, neutrophil activation, platelet activation, and alterations in coagulation-related proteins, which were closely mirrored in the SMAO model. Intravital microscopy revealed a dissociation between arterial and microvascular reperfusion: while arteriolar flow partially recovered after recanalization, venular perfusion remained severely impaired and was associated with early blood cell stasis and stable venular thrombus formation. Thrombi developed through a sequential process initiated during ischemia and amplified during reperfusion. Together, these findings identify venular-centered thrombo-inflammation as a key determinant of microvascular dysfunction and intestinal injury in arterial AMI, and provide a mechanistic framework for targeting thrombo-inflammatory pathways beyond arterial reperfusion that may extend to other clinical forms of AMI, including non-occlusive mesenteric ischemia (NOMI).