Melatonin Promotes Cerebral Angiogenesis in Ischemic Mice via BMP6/Smad1/5/9 Pathway

Angiogenesis facilitates the reinstatement of blood supply to cerebral tissues after stroke by reconstructing the vascular network, thereby rescuing the penumbra region and restoring neural functions. Melatonin can modulate angiogenesis under a variety of biological and disease-related states, and bone morphogenetic protein 6 (BMP6) targets regulators associated with angiogenesis. The specific functions of melatonin and BMP6 in angiogenesis following cerebral infarction, along with the potential intrinsic regulatory interactions between them, are currently unclear and need further investigation. Melatonin was given to the mice from the 1st day through the 28th day post permanent distal middle cerebral artery occlusion (dMCAO). Our research revealed that melatonin enhanced neurological performance and decreased the size of the brain infarction. Additionally, it boosted blood circulation and fostered angiogenesis in the penumbra area. Meanwhile, melatonin facilitated endothelial cells migration and tube formation after oxygen-glucose deprivation (OGD). Melatonin promoted the expression of BMP6 and its downstream targets, Smad1/5/9, as well as factors associated with angiogenesis Vascular Endothelial Growth Factor (VEGF) and Angiopoietin-1 (Ang1) in vivo and in vitro, which was counteracted or partially inhibited by suppression of BMP6 expression. Our research provides strong evidence that melatonin promotes angiogenesis after cerebral infarction through BMP6/Smad1/5/9 signaling pathway, supporting the restoration of neural function.