HMGB1 may act via RAGE to promote angiogenesis in the later phase after intracerebral hemorrhage

Abstract Following intracerebral hemorrhage (ICH), high-mobility group box 1 protein (HMGB1) may promote vascular remodeling. Whether HMGB1 supports angiogenesis after ICH is unclear, as are the receptors and downstream signaling pathway(s) involved. We used the rat model of collagenase-induced ICH to determine whether HMGB1 acts via the receptor for advanced glycation end-products (RAGE) to upregulate vascular endothelial growth factor (VEGF), a potent mitogen of endothelial cells and key regulator of normal and abnormal angiogenesis in the late phase of injury. At 3 d after ICH induction, rats were treated with saline, ethyl pyruvate (EP) or N-benzyl-4-chloro-N-cyclohexylbenzamide (FPS-ZM1). ICH induced the movement of HMGB1 from the nucleus into the cytoplasm. Levels of HMGB1 and RAGE in the ipsilateral striatum increased within a few days of induction and continued to rise for 7–14 d afterward. By 14 d after induction, levels of VEGF and vessel density were higher than in the Sham group. Administering EP 3 days after ICH induction prevented much of the stroke-induced increases in vessel density and in expression of HMGB1, RAGE, and VEGF. Administering FPS-ZM1 after ICH blocked much of the stroke-induced increases in vessel density and VEGF expression. Our results suggest that after ICH, HMGB1 may upregulate VEGF in the ipsilateral striatum predominantly via RAGE. Hence, targeting the HMGB1/RAGE signaling pathway may help reduce inappropriate angiogenesis after ICH.