Key mechanisms of angiogenesis in the infarct core: association of macrophage infiltration with venogenesis.

Angiogenesis in the ischemic penumbra compensates for microcirculatory dysfunction and promotes neuronal plasticity after stroke. However, the current understanding may be highly biased because the contribution of veins to angiogenesis has been overlooked. This study revealed that the remodeling processes of veins differ from those of arteries after ischemia. Ligation of the right jugular vein increased the infarct volume, decreased cerebral blood flow and impaired long-term functional restoration after stroke. RNA-seq analysis revealed significant upregulation of the expression of genes associated with angiogenesis in the infarct core during the recovery period. By using gelatin ink-alkaline phosphatase-oil red O (GIAO) staining, we found that venogenesis, the process of creating new veins, was the predominant angiogenic event in the infarct core. Macrophage infiltration and transformation are closely associated with venogenesis in the infarct core. However, depletion of macrophages in the circulation by clodronate liposomes in the acute phase inhibited the proliferation of endothelial progenitor cells and decreased the vascular density in the infarct core. This study demonstrated that dynamic vein remodeling is crucial for cerebral ischemic damage and subsequent neuronal restoration. Angiogenesis occurs in the infarct core during the recovery period, promotes the absorption of necrotic tissue and facilitates functional recovery after stroke.