HS intake impaired endothelium-dependent relaxation and transforming growth factor (TGF)-β receptor inhibition normalizes HS-induced endothelial dysfunction in Sprague-Dawley rats. Rats were fed with a LS or HS diet for 7 days and received either Veh or the ALK5 inhibitor SB beginning on day 5. Vascular responses were tested using aortae from the four groups of rats. A, left: contractile responses of aortic ring preparations to phenylephrine (Phe) did not differ among the four groups. Right, pEC50 values derived from the cumulative concentration-response curves did not differ among the four groups of rats in the study. B: cumulative concentration-response curves (left) were generated using ACh (0.001–10 μM) and used to calculate pEC50 values (right). HS intake significantly impaired endothelium-dependent relaxation, and ALK5 inhibition normalized this effect. Data are presented as means ± SE; n = 9 rats/group. *P < 0.05 vs. the HS SB group. C, left: pretreatment of ring preparations with Nω-nitro-l-arginine methyl ester (l-NAME) completely abolished ACh-dependent vasorelaxation. Right, responses of aortic ring preparations to sodium nitroprusside (SNP) did not differ among the four groups of rats.