 Environmental cues, such as physical forces and heterotypic cell interactions, have a significant impact on how cells behave. This study examined the effects of these factors on the transcriptional profile of human endothelial cells grown in both in vitro and in vivo conditions. The results showed that over 43% of the transcriptome was altered when the cells were grown in vitro, while another 17% of the transcriptome was restored when the cells were subjected to shear stress. Additionally, co-culturing the cells with smooth muscle cells helped restore the expression of nearly 10% of the original in vivo signature. Furthermore, this study identified several genes whose expression was affected by either the in vitro or heterotypic cell interaction environments, suggesting that contextual information plays a key role in regulating gene expression. This article was offered by Yelda Ofsho, Feiyan Ma, Austin Quach, and others.