HIF-2α Promotes Angiogenesis via VEGF/Notch1 Pathway and Exerts Neuroprotective Effects after Intracerebral Haemorrhage Injury.

Abstract Angiogenesis after intracerebral haemorrhage (ICH) injury can effectively alleviate brain damage and improve neurological function. HIF-2α is an important angiogenic regulator and shows protective effects in several neurological diseases, but its role in ICH has not been reported. We explored whether HIF-2α reduces ICH injury by promoting angiogenesis. In addition, we explored the role of the vascular endothelial growth factor (VEGF)/Notch1 pathway in HIF-2α-mediated angiogenesis. We injected 50 μL of autologous blood taken from the femoral artery into the right striatum area of healthy male adult Sprague-Dawley rats to create an autologous blood-induced rat ICH model. Lentiviral vectors were injected to overexpress and knock down HIF-2α expression. VEGFR2 and Notch1-specific inhibitors were injected intraperitoneally to block VEGFR2 and Notch1-mediated signalling after lentiviral injection. Our data showed that HIF-2α overexpression reduced neurological damage scores and brain water content, suggesting it had a protective effect on ICH injury. In addition, overexpression of the HIF-2α gene promoted angiogenesis, increased focal cerebral blood flow (CBF), and reduced neuronal damage. HIF-2α knockdown resulted in the opposite effect. Furthermore, HIF-2α-mediated angiogenesis was blocked by a Notch1-specific inhibitor. Likewise, the HIF-2α-mediated increase in VEGFR2 and Notch1 expression was reversed using a VEGFR2-specific inhibitor. Our study indicates that HIF-2α can promote angiogenesis via the VEGF/Notch1 pathway to attenuate ICH injury. These results may provide a new strategy to alleviate brain ICH injury by regulating HIF-2α to promote angiogenesis.