The expression of atheroprotective genes in vascular endothelium is regulated by key transcriptional factors (e.g., KLF2, KLF4, Nrf2) in response to hemodynamic, hormonal and environmental stimuli. The coordination of this genetic program is further influenced by miRNAs, epigenetic modifications, and pharmacologic agents. The resultant vasoprotective endothelial phenotype supports a spectrum of functions critical to the maintenance of vascular homeostasis.