Unveiling the VEGFR2-TTI1-mTORC1 Axis: A Crucial Pathway in Hypoxia-Induced Erythropoiesis

Erythropoiesis is a meticulously regulated process influenced by a multitude of factors. Prior research has demonstrated that hypoxic conditions (5% O₂) facilitate erythroid differentiation. Nevertheless, although our preliminary data indicate the involvement of VEGF/VEGFR2 in this process, the precise regulatory mechanism in erythropoiesis under hypoxia remains inadequately understood. In this study, an in vitro model of inhibited erythroid differentiation was developed using CD34⁺ hematopoietic stem cells treated with a VEGFR2-neutralizing antibody. Additionally, the signaling axis was modulated under hypoxia conditions employing the mTOR inhibitor rapamycin and TTI1-siRNA. The findings revealed that hypoxia significantly upregulated VEGF/VEGFR2 expression and promoted erythroid differentiation. Conversely, VEGFR2 inhibition resulted in a substantial decrease in erythroid surface markers and hemoglobin synthesis. Proteomics analysis suggested that TTI1 and mTOR are pivotal components of this signaling axis, with their suppression effectively impeding erythropoiesis. Under hypoxic conditions, VEGFR2 may regulate erythroid differentiation of CD34⁺ cells through a mechanism involving the TTI1-mTORC1 signaling pathway.