Andrographolide Promotes Post-Ischemic Endothelial Angiogenic Activity via IL-10-Mediated M2-Like Microglia–Endothelial Crosstalk Involving Endothelial VEGFR2 Upregulation

Ischemic stroke remains a leading cause of disability worldwide, and angiogenesis is critical for functional recovery. Although andrographolide (ANP) has anti-inflammatory and neuroprotective properties, its role in post-stroke angiogenesis remains unclear. Here, we investigated whether ANP promotes post-ischemic angiogenesis by modulating microglia–endothelial crosstalk. Using a ferric chloride (FeCl3)-induced carotid artery thrombosis model in male C57BL/6J mice, we found that ANP treatment (2.5 mg/kg) attenuated ischemic brain injury and neurological deficits, enhanced vascular stability, and improved cerebral blood perfusion. Mechanistically, ANP promoted a pro-reparative M2-like microglial state characterized by coordinated transcriptional changes, increased CD206 and IL-10, and reduced CD86 expression. ANP-treated microglia enhanced endothelial cell migration and tube formation while preserving tight-junction integrity through paracrine signaling. Co-immunoprecipitation and gain- and loss-of-function experiments further supported a microglial IL-10-dependent endothelial VEGFR2 upregulation. Together, these findings demonstrate that ANP promotes post-stroke reparative angiogenic activity through IL-10-mediated M2-like microglia–endothelial crosstalk involving endothelial VEGFR2 upregulation, linking its immunomodulatory effects to angiogenesis and highlighting microglia–endothelial crosstalk as a potential therapeutic target for ischemic stroke recovery.