The hemodynamic consequence of such increases in blood flow velocity

is to increase shear stress on the arterial wall, and to stimulate the endothelium to augment its production of NO and, possibly, other vasoactive molecules. Changes in the composition of the blood secondary to placental secretion of growth-promoting and vasodilatory AZD1208 in vitro signals such as estrogen, and growth factors such as VEGF, PlGF, and PDGF may act synergistically with the increased shear stress to further augment the expression and activity of endothelial NOS (eNOS or NOS-3). In this regard, eightfold increases in NOS activity have been documented during pregnancy in the human uterine artery [54]. NO production will promote vasodilation and reduce uterine vascular resistance, thereby tending to normalize shear stress on the arterial wall by allowing greater blood flow due to a larger lumen (albeit at a slower velocity) and may stimulate changes in both vascular smooth muscle and the extracellular matrix that

lead to outward expansive remodeling. Notably, changes in tone may lead to remodeling, as prolonged vasoconstriction has been shown to induce inward remodeling [40, 41]. If the corollary that vasodilation leads to outward remodeling is true, it may apply to the uterine circulation in pregnancy. The primary importance of the endothelium in mediating Selleck Ipatasertib flow-induced remodeling was first demonstrated in the carotid artery by Langille et al. [34] and confirmed in many subsequent studies [5, 33, 36, 72, 79]. These initial observations

highlighted the importance of shear stress in regulating arterial structural diameter and, as already mentioned, increased shear secondary to placentation have been suggested to play a role in the uterine Phosphoglycerate kinase circulation of hemochoriates [47]. For example, studies utilizing a surgical model that takes advantage of the parallel architecture of the mesenteric circulation to selectively raise flow by the ligation of alternate second-order arteries [62] have found that significant (20–30%) increases in diameter occurred over a period of two weeks in areas of increased flow. A series of studies has shown that the sequence of events that underlies the process of arterial structural remodeling involves an early inflammatory response characterized by macrophage infiltration of the arterial wall [2], followed by a rise in oxidative stress that favors the formation of ONOO− and activated matrix metalloproteinases, and subsequent degradation/remodeling of the extracellular matrix as well as changes in NOS-3 expression and NO production [44, 19, 80]. The production of other vasodilators (such as prostacyclin and carbon monoxide) may also occur. Although all of the studies published to date are in nonpregnant animals, Henrion and colleagues recently reported that ovariectomizing rats suppressed remodeling in vessels exposed to higher flow, whereas estradiol replacement (via an implanted osmotic pump) restored it [77].