Clinical and experimental evidence indicates that angiogenic imbalances may participate in the mechanisms of disease of several pregnancy complications, some of which may be life threatening. This article reviews current evidence in support of this view and the possibility that the fetus may play a central role in these imbalances; it also reviews recent experimental observations that modulation of angiogenic imbalances during pregnancy may have prophylactic and/or therapeutic value.
The human endothelium is considered the largest autocrine, paracrine, and endocrine organ, weighing 1.5 kg. This organ regulates vessel tone, platelet activation, monocyte adhesion, thrombogenesis, inflammation, lipid metabolism, and vessel growth and remodeling. A major property of vascular endothelial cells is the ability to proliferate and form a network of capillaries, which is a process that is known as angiogenesis. This is regulated by 3 families of growth factors that include vascular endothelial growth factors (VEGF), angiopoietins, and ephrins. Other factors include transforming growth factors α and β and its functional coreceptors (endoglin and soluble endoglin [s-Eng]), angiogenin, and members of the Notch family. However, VEGF signaling represents the rate-limiting step in physiologic angiogenesis. Indeed, endothelial cell proliferation and survival require continuous low levels of VEGF. The bioavailability of this angiogenic factor is thought to be regulated by antiangiogenic factors, which include the soluble form of VEGF receptor 1 (sVEGFR-1, also referred to as sFlt-1) in the nonpregnant and pregnant states. Indeed, in a pioneering study, Clark et al reported that a VEGF antagonist (sFlt-1) is produced by the human placenta and released into the maternal circulation. The authors reported that sFlt-1 messenger RNA (mRNA) was present in both villous and extravillous trophoblast, that sFlt-1 was released into the supernatants from placental villi cultures, and that serum from pregnant women was found to contain a VEGF-binding protein, which was identical to sFlt-1. The authors proposed that regulation of VEGF is essential to successful pregnancy. This proposal is consistent with accumulating evidence that indicates that imbalances between angiogenic factors (such as VEGF and placental growth factor [PlGF]) and antiangiogenic factors (such as soluble sVEGFR-1 and s-Eng) may participate in the mechanisms of disease of pregnancy complications.
An excess of antiangiogenic factors has been reported in patients with preeclampsia; placental abruption; HELLP syndrome; Mirror syndrome, which is associated with immune and nonimmune hydrops; preeclampsia associated with parvovirus and cytomegalovirus infections; twin-to-twin transfusion syndrome (TTTS); unexplained fetal death; as well as in women with fetal growth restriction or those who deliver small-for-gestational-age (SGA) neonates. In contrast, an excess of circulating angiogenic factors—specifically, free VEGF—has been described in ovarian hyperstimulation syndrome (OHSS) during pregnancy, which is a life-threatening condition that complicates 2.4% of pregnancies after in vitro fertilization.
Angiogenic imbalances in preeclampsia
Maynard et al reported a landmark study that provided experimental and clinical evidence that sVEGFR-1 is involved in the pathophysiology of preeclampsia. The authors reported (1) antiangiogenic properties in serum from pregnant women with preeclampsia, as demonstrated by the tube-formation assay; (2) high maternal serum concentrations of sVEGFR-1 among patients with preeclampsia; (3) up-regulation of VEFGR-1 mRNA in placentas from patients with preeclampsia; (4) lower concentrations of PlGF and free VEGF in patients with preeclampsia than in normal pregnant women; and (5) hypertension, proteinuria, and renal histologic findings that are similar to those described in patients who have preeclampsia with the administration of adenovirus, which expresses the sVEGFR-1 gene, to pregnant animals. More recently, it was reported that reduced uterine perfusion in pregnant nonhuman primates and rats is associated with hypertension and increased sVEGFR-1 placental expression. These observations are consistent with accumulating evidence that indicates the role of angiogenic-related factors in the pathophysiology of preeclampsia. Moreover, it has been proposed that the mechanisms by which nulliparity, twin pregnancies, and smoking increase or decrease the risk of preeclampsia can be explained on the basis of changes in the maternal serum concentration of antiangiogenic factors.
The conventional definition of preeclampsia is the presence of both gestational hypertension (systolic blood pressure, ≥140 mm Hg, or diastolic blood pressure, ≥90 mm Hg at least on 2 determinations) and proteinuria (≥300 mg in a 24-hour urine collection or 1 dipstick measurement ≥2+). Of note, recent studies indicate that gestational hypertension or gestational proteinuria are also associated with elevated maternal serum concentration of antiangiogenic factors. The authors proposed that these pregnancy complications may belong to the clinical spectrum of preeclampsia, which is a proposal that is supported by the observation that 25–50% of patients with gestational hypertension will develop preeclampsia. However, angiogenic imbalances may not be necessary or sufficient for the development of this pregnancy complication, because not all patients with preeclampsia have elevated plasma concentrations of antiangiogenic factors. Moreover, angiogenic imbalances are not limited to patients with preeclampsia. Indeed, elevated sVEGFR-1 or s-Eng had been described in patients with fetal growth restriction or delivering SGA neonates, fetal death, and TTTS. It is possible that the magnitude of the imbalances, genetic predisposition, or other factors may determine whether a patient with angiogenic imbalances will experience preeclampsia.
Changes in maternal plasma/serum concentrations of angiogenic-related factors occur before the presentation of preeclampsia. Indeed, elevated maternal serum/plasma concentrations of antiangiogenic factors has been described in the first and second trimesters in patients who experienced preeclampsia in the index pregnancy. Moreover, the determination of angiogenic factors in combination with uterine artery Doppler velocimetry and other parameters has been reported to play an important role in the identification of patients who are at risk to experience preeclampsia. For example, the combination of low maternal plasma concentration of PlGF and abnormal uterine artery Doppler velocimetry in the second trimester confers a very high risk for the development of early onset preeclampsia (<34 weeks of gestation; odds ratio, 43.8). Furthermore, a combination of maternal plasma concentrations of PlGF, uterine artery Doppler ultrasound, and other parameters in the first trimester identified 93.1% of patients who will experience preeclampsia that will require delivery before 34 weeks of gestation.
Angiogenic imbalances in Mirror syndrome
Mirror syndrome, or Ballantine’s syndrome, is referred to as the association of fetal hydrops with placentomegaly and severe maternal edema. This syndrome is also referred as “pseudotoxemia”; however, preeclampsia has been reported in approximately 50% of these cases. The term Mirror syndrome has been attributed to O’Driscoll, who reported that, in cases of fetal hydrops, “the mother to some degree mirrors the edema of the fetus.” This pregnancy complication was reported initially in cases of rhesus isoimmunization; however, it has also been described in other conditions that are associated with fetal hydrops including cytomegalovirus and parvovirus B19 infections, Ebstein’s anomaly, aneurysm of the vein of Galen, fetal supraventricular tachycardia, sacrococcygeal teratoma, and placental chorioangioma. Recent reports indicate that Mirror syndrome that is associated with immune and nonimmune hydrops, sacrococcygeal teratoma, and parvovirus infection is associated with angiogenic imbalances that are characterized by an excess of circulating sVEGFR-1 and/or s-Eng.
Villous edema is associated with high intracellular water content and high total placental water, which may limit the gas exchange in the fetomaternal interface. Indeed, the higher the proportion of edematous villi, the lower the pH in the arterial cord blood. The impaired oxygen exchange in the fetomaternal interface is most likely due to compression of the villous blood vessels and/or a thicker interface. However, swollen edematous villi may also reduce the intervillous space and the intervillous blood flow, with subsequent reduction in the fetal oxygen supply. Thus, severe villous edema in hydropic fetuses may be associated with trophoblast hypoxia/ischemia, which leads to placental overexpression and releases antiangiogenic factors.
Angiogenic imbalances in molar pregnancies and partial mole
Recent reports indicate that complete mole and partial mole with early-onset preeclampsia are associated with elevated maternal serum concentration of sVEGFR-1 and s-Eng. Of note, the serum concentrations of sVEGFR-1 in the first trimester among patients with complete mole are significantly higher than those from patients with normal pregnancies and those from patients who experienced preeclampsia in the index pregnancy. The authors proposed that elevated maternal serum concentrations of sVEGFR-1 increase the risk for early-onset preeclampsia among patients with complete mole. This is consistent with a historic comparison in New England that indicated that the prevalence of preeclampsia among patients with complete mole has significantly decreased from 12% (41/347 patients) in the period of 1966–1972 to 1.3% (1/74 patients) in the period of 1988–1993 ( P < .01), presumably because of earlier diagnosis and uterine evacuation, which may have prevented the subsequent development of preeclampsia.
Preeclampsia occurs in 41.9% of pregnancies with partial mole. The treatment of these cases is challenging and may require medical interruption of pregnancy if severe preeclampsia or HELLP syndrome develops. A recent report indicates that angiogenic imbalances, which are characterized by high maternal serum concentrations of sVEGFR-1 and s-Eng and low circulating free VEGF, may participate in the pathophysiology of preeclampsia that is associated with partial mole.
The conventional view is that placental villi in partial and complete mole are “avascular” or limited to villous capillary remnants. However, this notion was challenged recently by the observation that vascular endothelial cells are present in the villous stroma of complete moles. These inconsistencies may be due to histologic heterogeneity, which is known to occur in placental studies.
The onset of placental hypoperfusion because of uteroplacental ischemia may determine the timing of the clinical presentation of preeclampsia. Indeed, accumulating evidence indicates that chronic uteroplacental ischemia is more relevant in the pathogenesis of early-onset preeclampsia than in term or postterm preeclampsia. This view is supported by the observation that high impedance to blood flow in both uterine arteries in the second trimester (a surrogate marker of chronic uteroplacental ischemia) is associated with a higher risk for preeclampsia at ≤34 weeks than at >34 weeks of gestation. To the extent that placental villi in partial or complete mole are limited to villous capillary remnants, molar pregnancies that are complicated by preeclampsia may represent an extreme in the spectrum of ischemic disease of the trophoblast. Thus, it should not be surprising that preeclampsia frequently occurs at <20 weeks’ gestation in these patients.
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