Regulation of Maternal Blood Pressure by the Conceptus During Early Pregnancy

Pregnancy has a profound impact on the homeostatic regulation of maternal systemic arterial pressure in humans [1, 2]. During the first trimester, prior to substantial blood flow through the placenta [3], there is a decrease in systemic vascular resistance likely caused by systemic vasodilation. This is accompanied by an increase in both plasma volume and cardiac output, but these are not sufficient to maintain maternal arterial pressure. The net result is a characteristic decrease in maternal mean arterial pressure through mid-gestation of pregnancy. Several mechanisms have been suggested for these cardiovascular changes, including modulation of the reninangiotensin system and increased nitric oxide production [1]. However, complete understanding of the mechanisms involved remains to be determined. Elucidation of these mechanisms may be crucial to understanding several important complications of human pregnancy such as preeclampsia, a condition clinically defined by elevated maternal blood pressure and proteinuria, associated with maternal arterial stiffness [4]. Many human obstetrical complications such as preeclampsia become clinically evident only later in gestation but are likely the result of abnormalities that occur early in gestation. Clearly, animal studies are critical to determine the mechanisms responsible for these cardiovascular changes, as it is impossible to adequately address causality directly in humans for obvious ethical reasons. In a fashion similar to that of humans, mice also exhibit the characteristic decrease in maternal arterial pressure after the onset of implantation through to mid-gestation [5–9]. This is the period of time when major changes occur in the uterus and the developing placenta but before there is much placental blood flow. Initial studies evaluated the potential role of uterine natural killer (uNK) cell-driven spiral artery modification in mediating the drop in mean arterial pressure in early pregnant mice [10]. This work suggested that uNK cells have the potential to take part in the decrease in maternal mean arterial pressure leading to mid-gestation. However, studies by Barrette et al. [11] demonstrated that the decline in blood pressure occurred normally in Rag2 / cc / mice; these mice lack uNK cells and, thus, the characteristic spiral artery modification of pregnancy. These findings suggested that conceptus-derived signals are required. Work published in the current issue of Biology of Reproduction by Barrette et al. [11] sought to answer the important question of whether the decrease in maternal mean arterial pressure occurs in uteri undergoing artificially induced decidualization in the absence of the conceptus. The authors used radiotelemetry and a model in which blastocyst-sized concanavalin A-coated agarose beads were used as a deciduogenic stimulus. This method of inducing a deciduoma has previously been shown to be more physiologically relevant than other generally used artificial stimuli [12]. Surprisingly, Barrette el al. [11] found that the decrease in maternal mean arterial pressure leading up to midpseudopregnancy does not occur in the deciduoma-bearing mice lacking a conceptus. This provides strong evidence supporting the hypothesis that signals from the conceptus initiate the decrease in maternal arterial pressure through midgestation in mice. The work of Barrette et al. [11] further provides an important proof-of-principle that conceptus-derived factors play a key role in driving maternal cardiovascular changes during early pregnancy. Because they are in direct contact with the mother, the source of the signals involved may be trophoblast cells. Indeed, mouse trophoblasts [13, 14], like human trophoblasts [15], are known to produce many vasoactive substances which could act systemically on maternal vessels. However, one cannot rule out the possibility that nonvasoactive factors from the conceptus may also regulate downstream maternally expressed vasoactive substances either in a paracrine or endocrine fashion. An exciting possibility brought up by Barrette et al. [11] is that microparticles and nanoparticles shed by trophoblasts may be involved. Microparticles are produced by human placentae during normal pregnancy, and production is generally thought to increase in diseases such as preeclampsia [16]. Depending upon their contents, microparticles can either augment or inhibit vascular functions [17]. Although demonstrated in humans, the presence of trophoblast microparticles in the maternal circulation or uterus have yet to be demonstrated during early pregnancy in mice. Presently, more work is required to determine the precise identity, function, source, and regulation of conceptus-derived factors involved in the decrease in maternal arterial pressure during early pregnancy.