Figure 9. Hypoxia stimulates VEGF/Notch signaling by downregulating miR-203a-3p expression. (A) Hypoxia upregulates the expression of VEGF-A and downregulates the expression of its negative regulator miR-203a-3p (red box). (B) VEGF-A binds and activates VEGFR2 in tip cells, leading to the activation of the Dll4 promoter (purple box). (C) Dll4 activates Notch1 receptor in neighboring stem cells. Gamma secretase (GS) cleaves the Notch1 receptor intracellular domain (NICD), which is transferred to the nucleus to enhance the expression of transcription factors (TFs) such as Hes-1. These TFs inhibit the expression of VEGFR2 in stem cells and promote the expression of downstream genes that regulate budding, proliferation, and differentiation of PMVECs (blue box).