Angiogenesis plays a vital role in cerebral tissue repair following ischemic stroke. Prior in vivo studies have identified astrocytic interleukin-17A (IL-17A) as a critical mediator of post-ischemic angiogenesis, associated with upregulation of interleukin-6 (IL-6) and vascular endothelial growth factor (VEGF). However, the intracellular signaling mechanisms underlying these effects within astrocytes have not been fully elucidated. This study delineates a specific intracellular signaling mechanism through which astrocytic IL-17A promotes angiogenesis following an in vitro ischemia-like injury. Primary astrocytes were exposed to oxygen-glucose deprivation followed by reperfusion (OGD/R). Astrocyte viability was assessed using the Cell Counting Kit-8 assay. Brain microvascular endothelial cells (BMECs) were cultured with astrocyte-conditioned medium (ACM). Astrocytes were treated with recombinant IL-17A (rIL-17A), IL-17A-targeted small interfering RNA, a neutralizing antibody against IL-6, or the Janus Kinase 2/Signal Transducer and Activator of Transcription 3 (JAK2/STAT3) pathway inhibitor AG490. Protein levels were quantified, and angiogenic capacity was determined via tube formation assays and CD34 expression analysis. Exposure to OGD/R increased IL-17A secretion from astrocytes. Treatment with rIL-17A enhanced astrocyte viability and induced IL-6 production. Activation of the JAK2/STAT3 pathway by IL-6 was required for the subsequent VEGF upregulation. Consequently, ACM from rIL-17A-treated astrocytes significantly promoted angiogenic activity in BMECs, as evidenced by enhanced tube formation. These pro-angiogenic effects were significantly attenuated by IL-17A knockdown, IL-6 neutralization, or inhibition of JAK2/STAT3 signaling in astrocytes. This study delineates a specific intracellular signaling mechanism through which astrocytic IL-17A promotes angiogenesis following ischemia-like injury. The findings identify an IL-6-dependent activation of the STAT3-VEGF signaling axis as a key mediator of this process, underscoring the therapeutic potential of targeting astrocytic IL-17A signaling in post-stroke angiogenic repair.
Chen et al. (Mon,) studied this question.