The article discusses the molecular mechanisms controlling endothelial cell (EC) behavior during blood vessel morphogenesis, focusing on angiogenesis. It highlights the role of key signaling pathways such as vascular endothelial growth factor (VEGFA) and Notch in regulating EC behavior during blood vessel sprouting. VEGFA is the principal master regulator of new blood vessel sprouting, while Notch signaling plays a critical role in determining the fate of ECs, such as tip cells (TCs) and stalk cells (SCs). The study also explores the interactions between ECs and mural cells, including pericytes and vascular smooth muscle cells, which are essential for vascular stabilization and maturation. The article emphasizes the importance of spatial and temporal regulation of VEGFA isoforms and the role of various signaling pathways, including those involving Netrins, ROBO receptors, and Semaphorins, in guiding EC migration and vessel formation. Additionally, it discusses the post-transcriptional and post-translational mechanisms that fine-tune angiogenic responses, such as the role of microRNAs in regulating VEGF signaling. The study also highlights the significance of mechanosensitive pathways in integrating blood flow and VEGFR signaling during vascular remodeling. Overall, the review underscores the complexity of angiogenesis and its relevance to various biological processes, including tissue branching and mechanotransduction.The article discusses the molecular mechanisms controlling endothelial cell (EC) behavior during blood vessel morphogenesis, focusing on angiogenesis. It highlights the role of key signaling pathways such as vascular endothelial growth factor (VEGFA) and Notch in regulating EC behavior during blood vessel sprouting. VEGFA is the principal master regulator of new blood vessel sprouting, while Notch signaling plays a critical role in determining the fate of ECs, such as tip cells (TCs) and stalk cells (SCs). The study also explores the interactions between ECs and mural cells, including pericytes and vascular smooth muscle cells, which are essential for vascular stabilization and maturation. The article emphasizes the importance of spatial and temporal regulation of VEGFA isoforms and the role of various signaling pathways, including those involving Netrins, ROBO receptors, and Semaphorins, in guiding EC migration and vessel formation. Additionally, it discusses the post-transcriptional and post-translational mechanisms that fine-tune angiogenic responses, such as the role of microRNAs in regulating VEGF signaling. The study also highlights the significance of mechanosensitive pathways in integrating blood flow and VEGFR signaling during vascular remodeling. Overall, the review underscores the complexity of angiogenesis and its relevance to various biological processes, including tissue branching and mechanotransduction.