Many of the initial changes (e.g., inflammation, oxidative stress, or MMP expression) were not estrogen-dependent, but estrogen was required for the increase in NOS-3 JAK inhibitor expression and activation, events that normally occur

at the time that diameter expansion begins several days after the initiation of increased flow. Based on these studies, it seems likely that pregnancy-induced increases in circulating estrogen may not only facilitate uterine vascular remodeling but also amplify arterial circumferential growth in response to increased shear stress in upstream vessels, as summarized in Figure 3. Endocrine and other influences could also be expected to modify other endothelial vasodilator (especially NO-mediated) signaling systems. There are, however, several caveats that deserve RAD001 mouse mention. First, there is evidence that shear stress is not normalized in the

main uterine artery of women in week 36 of pregnancy, as velocity was nearly eight times faster than in the nonpregnant state, whereas diameter was only increased twofold [61]. Second, as already mentioned, some remodeling occurs in uterine arteries early in pregnancy, prior to the initiation of placental blood flow. It is not known whether arteriovenous anastomoses already exist and increase flow at this point in gestation; if they do, shear would be increased independently of the placenta. Third, in rats, both pre-myometrial and pre-placental radial arteries widen significantly [12, 25] whereas placentation-induced reductions in Non-specific serine/threonine protein kinase downstream resistance would presumably only directly affect the latter. It is conceivable that there

may be a venoarterial pathway by which placental signals pass through the venous wall and stimulate arterial dilation and/or growth. Although this pathway has been well established in luteolysis [23], its physiological relevance to pregnancy-induced remodeling has yet to be examined in vivo. As already noted, significant axial growth (arterial lengthening) of both arteries and veins occurs in the uterine circulation during pregnancy, and this process is completely unaffected by NOS inhibition [55]. Although the mechanisms that stimulate arterial axial remodeling are not known, a recent study from one of our laboratories [56] indicated that myometrial stretch or deformation such as occurs secondary to the growth of the conceptus might, in and of itself, be a potent stimulus for arterial longitudinal growth. In the years ahead, additional research is needed to elucidate the mechanisms that regulate axial as well as circumferential arterial growth during gestation, as well as the growth of uterine veins.