Stimulatory effects of progesterone and estrogen hormones together with a higher basal metabolic rate increase maternal ventilatory sensitivity to chemosensory stimuli and raise MLN8237 concentration ventilation by 25% [53]. The greatest changes, however, are those occurring in the uteroplacental circulation, where an even greater fall in vascular resistance preferentially directs some 20% of total cardiac output to this vascular bed by term, amounting to a >10-fold or greater increase over levels present in the nonpregnant state such that, by term, uteroplacental flow may approach 1 L/min [61]. Many of these changes are complex, distinctive,

and subject to particular, local control. The purpose of this review is to describe the remodeling process that enables the progressive and substantial increase in uteroplacental blood flow required for normal fetal growth and development. Most broadly, the remodeling process can be viewed as a combination of changes in vascular structure, which result in increased vessel diameter and length, and concurrent changes in vascular function, i.e., altered vasoreactivity (including Adriamycin clinical trial myogenic tone). Ultimately, this combination of passive structure and superimposed

active tone regulate arterial lumen diameter, the primary physiological determinant of vascular resistance and, hence, blood flow to the uteroplacental circulation. With the exception of the endometrium, the vascular system of the adult is largely quiescent. Structural changes that do occur with age, such as arterial stiffening and plaque formation, are generally pathological in nature as they may lead to the development of hypertension and atherosclerosis, respectively. Endometrial changes are cyclic with each menstrual cycle and involve only the microcirculation. Hence, the significant growth of the maternal vessels

during pregnancy represents a unique physiological event whose understanding can be approached from the standpoint of underlying processes and associated events, signals and pathways (Figure 1). Much of this review is focused on the structural changes that occur in arteries and veins, i.e., true structural oxyclozanide remodeling, whose pattern is most often referred to as being outward (or expansive) and hypertrophic [59]. The latter term derives from the fact that the most common pattern is one of luminal enlargement with little or no change in wall thickness (with the exception of the mouse [81, 82]). Without any change in wall thickness, cross-sectional area will increase secondary to the larger lumen and result in a greater overall tissue mass. Put differently, eutrophic lumenal expansion requires a reduction in wall thickness to maintain a constant cross-sectional area whereas hypertrophic expansion accomplishes an increase in diameter without any change in wall thickness (although total cross-sectional area is still increased).