These mice develop hypertension in part via functional changes to VSMC and this indicates an essential role of Rap1 (and possibly Epac) in maintaining normal vascular physiology.30 With regard to the Rap1-induced inhibition of RhoA, other studies have previously demonstrated this link although not in relation to VSMC migration.21 We now provide evidence of the importance of this Rap1/RhoA mechanism in a pathologically relevant process and this is summarized in Figure 7. This evidence concerns the gene RAPGEF4 and hypertensive disorder.