Uterine vascular adaptations such as vessel growth and vasodilation are needed to facilitate the more than 10-fold increase of uteroplacental blood flow (UPBF) during pregnancy. Adverse adaptations may result in pregnancy complications such as preeclampsia and intrauterine growth restriction. Pregnancy milieu, placentation and the attendant change in wall shear stress are major regulators of uterine vascular adaptation. In this study, we aimed at delineating : (1) the contribution of these regulators in vascular remodeling and (2) the effects of pregnancy milieu (estrogen and progesterone) alone and in combination with wall shear stress on the vascular reactivity. Using Sprague Dawley rats as the animal model, three surgical methods were utilized: (1) unilateral oviductal ligation (OHL) that restricts pregnancy to one uterine horn; (2) cervical-end main uterine artery and vein ligation (VL) that alters the hemodynamic pattern of the UPBF and wall shear stress; and (3) ovariectomy (OVX) with the implant of estrogen + progesterone pellet (0.5 and 100 mg, respectively). A segment of ovarian-end main uterine artery from each uterine horn was dissected, cannulated, and pressurized in an arteriograph system. Lumen diameters in response to phenylephrine (vasoconstrictor) and acetylcholine (vasodilator) were measured. Passive lumen diameters, wall thickness, vessel cross-sectional area, and distensibility were also measured under a microscope. Significant remodeling was seen in OVX rats in response to hormone replacement (p=0.0457); however, the extent of remodeling did not reach that seen in the nonpregnant horn of OHL rats. No significant change in wall thickness, cross-sectional area or wall: lumen ratio was found in OVX (+pellet), compared to OVX (-pellet) rats. Estrogen + progesterone had no significant effect on the sensitivity to phenylephrine or acetylcholine. In conclusion, estrogen + progesterone does have a significant effect on vascular remodeling. The presence of other factors, such as placentation, likely augment this process