SUMMARY Arteries and veins play different roles in human physiology and vascular diseases. Notably, arterial and venous endothelial cells (ECs) demonstrate distinct molecular profiles. The establishment of such molecular distinction is orchestrated by series of transcriptional programs, which have been well studied in developmental biology. However, how these EC transcriptional programs control adult blood vessel structure and function, and how to translate this knowledge into clinical application such as vein or tissue engineered graft adaptation is under- explored. To address this question, we examined the transcription profile of arterial vs. venous ECs in adult blood vessels and have identified several key transcription factors that are differentially expressed in arterial vs. venous ECs. Among them, Sox13 and Sox17 are highly expressed in adult arterial ECs but not in venous ECs. Our preliminary studies demonstrate that over-expressing Sox17 in venous ECs reconstitutes all the known arterial markers, suggesting Sox17 is a key regulator of adult arterial EC phenotypes. Importantly, Sox17 induces the expression of multiple families of molecules (Notch, Ephrin, Connexins, PDGF) that may confer signals from ECs to smooth muscle cells (SMCs) to regulate SMC phenotypes in blood vessels. EC Sox17 also promoted SMC contractile phenotype in EC-SMC co-culture and graft remodeling model. On the other hand, over-expressing Sox13 in ECs facilitates the recruitment of SMCs toward blood vessels. Based on these encouraging preliminary data, we hypothesize that endothelial Sox13/17 play synergistic roles in the homeostatic regulation of adult artery functions by maintaining adult arterial EC phenotype and engaging EC- SMC crosstalk. To test this hypothesis, we will investigate how the endothelial Sox13/17 regulates EC and SMC phenotypes and their role in blood vessel structures and functions using in vitro bioengineered models as well as in vivo animal models.