Vertebrate development depends on the formation of a closed circulatory loop consisting of intricate networks of veins, arteries, and lymphatic vessels. The coordinated participation of multiple molecules including growth factors, transcription factors, extracellular matrix proteins, and regulators of signaling such as small GTPases is essential for eliciting the desired cellular behaviors associated with vascular assembly and morphogenesis. We have recently demonstrated that a novel transcriptional pathway involving activation of the Epidermal Growth Factor-like Domain 7 (Egfl7) gene by the transcription factor CASTOR (CASZ1) is required for blood vessel assembly and lumen morphogenesis. Furthermore, this transcriptional network promotes RhoA expression and subsequent GTPase activity linking transcriptional regulation of endothelial gene expression to direct physiological outputs associated with Rho GTPase signaling, i.e., cell adhesion and cytoskeletal dynamics. Here we will discuss our studies with respect to our current understanding of the mechanisms underlying regulation of RhoA transcription, protein synthesis, and activity.