During pregnancy, the placenta has important nutritional, metabolic, and endocrine functions that constitute the link between the mother and the fetus. The transfer of oxygen and essentials nutrients from maternal blood to the fetal bloodstream requires an adequate uterine perfusion and a placental vascular network. Abnormalities in these processes are associated with an increased risk for miscarriage, preterm delivery, preeclampsia, and fetal growth restriction (FGR) (Regnault et al., 2002).

The formation of blood vessels involves two consecutive processes: (1) vasculogenesis, which involves the structuring of primitive vessels from mesenchymal cells; and (2) angiogenesis, which is the generation of new blood vessels from preexisting vessels to form the vascular placental network (Charnock-Jones et al., 2004). Both processes are driven and regulated by multiple factors, including oxygen concentration, growth factors, cytokines, and steroid hormones. Sex steroids are essential to maintain a normal pregnancy, and they participate in the control of a wide range of maternal and placental functions as well as in the normal development of fetal organs such as the lungs and adrenal glands (Seaborn et al., 2010; Ishimoto and Jaffe, 2011). Moreover, variations in maternal serum concentrations of sex steroids have been described in conditions associated with abnormal placentation that impact placental perfusion, thus leading to pregnancy-related pathologies. Therefore, the aim of the present review is to summarize the current knowledge regarding the role of progesterone, androgens, and estrogens in the uterine-placental vasculature.

During pregnancy, uterine blood flow increases dramatically mainly through a decrease in the uterine vascular resistance as a result of uterine arteries dilation and remodeling. Many of these effects are produced by changes in the muscular tone of uterine arteries that are mediated by the action of nitric oxide (NO) and prostanoids (prostacyclins, prostaglandins, and thromboxane). NO increases uterine blood flow through the relaxation of uterine arteries by a mechanism that involves a decrease in intracellular Ca²⁺ concentrations (i[Ca²⁺]) in vascular smooth muscle cells (VSMC). NO originates from the metabolism of L-arginine by the action of endothelial NO synthase (eNOS) in endothelial cells. Prostacyclin (PGI2) also induces vasodilation. However, has been observed that PGI2 exerts a compensatory action when NO production is reduced (Beverelli et al., 1997). Prostaglandin F2α (PGF2α) and thromboxane A2 (TXA2) induce vasoconstriction. Prostanoids are produced by the action of the cyclooxygenase (COX) enzymes, COX-1 and COX-2, on arachidonic acid. Of note, during pregnancy, serum concentrations of PGI2 increase dramatically, whereas PGF2α and TXA2 remain constant, thus favoring vasodilation (Mills et al., 1999).

Other regulators of the uterine vascular tone during pregnancy include adrenomedullin (Ross et al., 2010) and the components of the renin-angiotensin system, mainly angiotensin-(1–7) (Merrill et al., 2002). In rat uterine arteries, adrenomedullin induces relaxation mediated by the NO–cGMP-pathway (Ross et al., 2010). Angiotensin (1–7) is released from syncytiotrophoblasts, which act as a potent vasodilator in contrast to angiotensin II, which induces vasoconstriction (Valdes et al., 2006).

The placenta originates from the differentiation of trophoblastic cells from the pre-implantation embryo into cytotrophoblasts and syncytiotrophoblasts (Gerbaud and Pidoux, 2015). Two weeks after conception, the blastocyst cells acquire the ability to invade and migrate through the endometrial wall. The decidualization reaction of stromal endometrial cells subsequently results in an important increment in tissue permeability and vascular density. This reaction favors the migration of extravillous cytotrophoblasts (EVT) across the decidua to reach the endothelial cells of the terminal segments of the uterine arteries occluding their lumen (Figure 1), which restricts blood flow into the intervillous space and leads to a drop in oxygen concentration (Figure 1). Between weeks 11–12 until weeks 18–20 of gestation, EVT remodel the uterine spiral arteries. The remodeling allows the uterine spiral arteries to acquire a large capacitance and low resistance, thus gradually increasing maternal blood flow and oxygen levels (Rodesch et al., 1992).

The growth and development of the placental vascular network occurs through branching angiogenesis, which involves the formation of new vessels by the sprouting of preexisting vessels and a subsequent increase in the number of capillaries; it also occurs through non-branching angiogenesis, which involves the elongation of vessels and leads to the formation of capillary loops (Charnock-Jones et al., 2004).

The members of the vascular endothelial growth factor (VEGF) family are central in the regulation of placental vasculogenesis and angiogenesis (Demir et al., 2004). VEGF family members are produced by trophoblastic cells, Hofbaur cells, and maternal decidual cells (Figure 1) (Clark et al., 1996). The VEGF family has five members encoded by individual genes, including VEGF-A, VEGF-B, VEGF-C, VEGF-D, and PlGF (placenta growth factor). VEGF-A increases vascular permeability in endothelial cells, inducing placental vasculogenesis, and angiogenesis. Moreover, VEGF-A stimulates the expression of placental eNOS and NO production, thus inducing vasodilatation and promoting endothelial cell proliferation (Papapetropoulos et al., 1997) (Figure 1).

In general, VEGF-A, VEGF-B, and PlGF bind to VEGFR-1 (or Flt-1), whereas VEGF-A also binds to VEGFR-2 (or KDR). VEGF-A exhibits an increased affinity for Flt-1. However, KDR is more active in angiogenic stimulation (Stuttfeld and Ballmer-Hofer, 2009). In the human placenta, Flt-1 is located in syncytiotrophoblasts and endothelial cells of the placental villi (Helske et al., 2001). On the other hand, KDR is almost exclusively expressed in endothelial cells, which mostly occurs during the first trimester of gestation in parallel to the high angiogenic activity at that time (Yamazaki and Morita, 2006). The action of VEGF on angiogenesis is regulated by an impressive paracrine negative feedback system in which the soluble form of Flt-1 (sFlt-1) acts as a potent inhibitor of angiogenesis that is regulated by VEGF.

The hypoxic environment induces the expression of factors regulating the angiogenesis process, and hypoxia-inducible factor (HIF)-1α is one of the main factors (Kingdom and Kaufmann, 1999). Of note, villous trophoblasts cultured under hypoxic conditions (1% O₂) express high levels of VEGF-A, Flt-1, and sFlt-1 mRNA (Munaut et al., 2008). Interestingly, recent evidence suggests that HIF-1α is also activated by non-hypoxic stimuli, such as growth factors, immunogenic cytokines, and sex steroids (Patel et al., 2010).

Other regulators of placental angiogenesis include angiopoietin (Ang)-1, Ang-2, and their receptor Tie-1. These proteins are complementary to the VEGF system but participate in the later stages of angiogenesis. In early pregnancy, Ang-2 is more highly expressed than Ang-1. However, Ang-2 decrease during the course of pregnancy (Geva et al., 2002). Finally, endoglin (Eng), a homodimeric transmembrane glycoprotein that belongs to the TFG-β (transforming growth factor beta) complex, contributes to placental angiogenesis; however, a placenta-derived soluble endoglin isoform (sEng) acts as an anti-angiogenic protein that inhibits TGF-β1 signaling in endothelial cells.

The role of progesterone and estrogen in the regulation of the uterine vascular tone has been recognized for a long time. However, the effects of testosterone have only been recently addressed. In the placenta, androgens are metabolized to estrogens by the P450 aromatase. Dihydrotestosterone (DHT), which cannot be metabolized to estrogen, is subsequently reduced by aldo-keto reductase family 1 C into androstenediol (5α-androstane-3β, 17β-diol [3β-diol]), which has estrogen-like activity through ERβ (Lund et al., 2004). Therefore, androgenic and estrogenic effects cannot be easily separated in this tissue.

The role of sex steroids in placental angiogenesis has not been widely studied. Preliminary evidence suggests that sex steroids can regulate both endometrial and placental angiogenesis.

An abnormal blood supply to the uterine-placental region leads to early miscarriage, preterm delivery, preeclampsia, and FGR. In this regard, modifications to the circulating levels of sex steroids and/or uterine and placental sex steroids receptors are associated with poor obstetric and prenatal outcomes.

Women with unexplained recurrent pregnancy loss exhibit elevated uterine arterial impedance, which is negatively correlated with circulating progesterone levels. Of note, the administration of dydrogesterone, a synthetic progestin, reduced the resistance to blood flow in the uterine arteries, suggesting that insufficient progesterone action could be involved in a poor uterine blood supply and lead to miscarriage (Habara et al., 2002). Moreover, the elevated expression of Dickkopf-related protein-1 and low expression of PR-A have been observed in women with unexplained recurrent spontaneous miscarriage (Papamitsou et al., 2011; Bao et al., 2013). On the other hand, in growth-restricted pregnancies, PR expression in the placental tissue is positively correlated with IGF-1 expression and infant anthropometry, and it is independent of the presence of pregnancy pathologies (Akram et al., 2011). A group of studies has demonstrated that preeclampsia is associated with increased levels of progesterone along with increased expression of CYP11A, which inhibits trophoblastic proliferation and potentially the production of prostacyclin; this association affects the development of placental vasculature (Walsh and Coulter, 1989; He et al., 2013). Another group of studies demonstrated low circulating levels of progesterone and aldosterone in women with preeclampsia affected the secretion of endothelin-1, which is a potent vasoconstrictor. These results indicate that progesterone could be involved in the maintenance of normal blood pressure (Kiprono et al., 2013; Uddin et al., 2014). Therefore, normal development of placental vasculature is potentially dependent on physiological ranges of progesterone concentrations.

Because estrogen is an important regulator of uterine blood flow and the production of angiogenic factors in placental tissue, it is possible to hypothesize that estrogens are involved in the pathophysiology of pregnancy-related pathologies. At the 27th gestational week, estriol is positively associated with birth weight, birth length, and placental weight (Wuu et al., 2002). However, in rats, pharmacological doses of estradiol benzoate induce growth restriction, the reduction of placental weight, and trophoblastic degeneration (Matsuura et al., 2004). ERβ appears to be an important inducer of vasoconstrictor prostanoids because it increases the resistance of the feto-placental blood flow (Su et al., 2011).

Elevated androgen levels are a recurrent finding in preeclamptic women (Troisi et al., 2003; Salamalekis et al., 2006; Sharifzadeh et al., 2012), and this finding is likely related to a sex-related dysregulation in P450 aromatase (Steier et al., 2002; Sathishkumar et al., 2012). In women with polycystic ovary syndrome, which causes elevated androgen levels during pregnancy, the placenta presents an abnormal uterine blood flow as well as placentation with reduced endovascular trophoblast invasion (Palomba et al., 2010, 2012, 2013). Interestingly, placental tissues from these patients exhibit increased ERα expression (Maliqueo et al., 2015). Therefore, abnormalities observed in PCOS women could be attributed to estrogen or androgen action. However, it is not clear whether these alterations are directly associated with elevated androgen levels, as PCOS mothers also exhibit elevated insulin levels and a pro-inflammatory pattern (Sir-Petermann et al., 2007; Palomba et al., 2014), which may also influence placental function.

Adequate uterine perfusion is necessary to achieve successful implantation. Moreover, placental vasculogenesis and angiogenesis ensure optimal transfer of oxygen and nutrients along with fetal detoxification. All these processes are essential for an adequate fetal development. The available data clearly note that sex steroids contribute to the modulation of uterine blood flow through the regulation of uterine vessels and placental vasculogenesis and angiogenesis, which involves controlling trophoblast invasion and the remodeling of uterine arteries.

MM conceived and wrote the manuscript; BE and NC contributed with the writing and revised critically the manuscript.

This work was supported by Fondo Nacional de Desarrollo Científico y Tecnológico (National Fund for Scientific and Technological Research; Fondecyt; Grant 11130250 and 11130126).