This issue of the Journal of Maternal-Fetal & Neonatal Medicine contains several articles on the subject of angiogenic and anti-angiogenic factors in preeclampsia and small for gestational age (SGA). The subject has become topical. Indeed, there are hopes that assessing the concentration of angiogenic and anti-angiogenic factors will help predict preeclampsia and SGA, and also, that the blockade of anti-angiogenic factors or administration of angiogenic factors may be a therapeutic breakthrough for these complications of pregnancy Citation[1].
The importance of blood vessel formation in pregnancy
The development of new blood vessels is essential for mother and fetus. The fetus must develop a circulation if it is to develop and survive. The mother must increase the blood supply to support the placenta and fetus.
Most of the research in angiogenesis over the last few decades has been conducted by tumor biologists upon the realization that a vascular supply is required for tumor growth. Scientific giants, such as Judah Folkman, have pioneered this field with the hope that inhibitors of angiogenesis will be successful in preventing tumor growth Citation[2-4].
Investigators have drawn parallels between the capacity of tumors to induce blood vessel formation and a similar phenomenon in pregnancy Citation[5]. Both conditions result in the access of the host vasculature to ensure blood supply. However, there are two crucial differences between tumors and pregnancy: (1) new vessel formation and invasion during pregnancy is self-limited; (2) the embryo forms its own blood vessels while tumors do not.
Vasculogenesis and angiogenesis
Two processes are essential for vascular development: vasculogenesis and angiogenesis. Vasculogenesis is the formation of a primitive vascular network from endothelial progenitor cells or angioblasts. Angiogenesis is the development of new vessels from pre-existing ones. Two forms of angiogenesis are recognized: sprouting and non-sprouting. The reader is referred to the excellent reviews on the subject by Charnock-Jones, Kaufmann, and Mayhew, with a focus on feto-placental development Citation[6-8].
The role of angiogenic and anti-angiogenic factors
The regulation of angiogenesis is under the control of a number of growth factor families including the vascular endothelial growth factor (VEGF), angiopoietins, and ephrins Citation[9]. However, other factors include fibroblast growth factors, interleukin-8, hepatocyte growth factor, angiogenin, transforming growth factors α and β, tumor necrosis factor α, etc. Citation[10-12]. The molecular basis for lymphangiogenesis has been the subject of recent attention Citation[13],Citation[14]. Similarly, progress has been made in identifying what signals are responsible for venous specification. For example, the orphan receptor COUP-TFII regulates venous specification. The homeobox gene Prox-1 is a master switch of lymphatic commitment Citation[15-17].
The importance of the VEGF family for embryo development is demonstrated by the fact that a heterozygous knockout is lethal Citation[18],Citation[19]. The placenta can be considered fundamentally as a vascular organ for the exchange of oxygen and nutrients. Without blood vessels there is no functioning placenta (i.e., complete hydatidiform mole). This organ is a rich source of angiogenic factors Citation[20],Citation[21], some of which can be detected in the maternal circulation (angiogenic and anti-angiogenic factors have paracrine and endocrine function).
An anti-angiogenic state as a mechanism of disease during preeclampsia and SGA
The idea that an imbalance between angiogenic and anti-angiogenic factors could cause disease in pregnancy has been proposed by several investigators Citation[20-45]. However, the laboratory of Ananth Karumanchi at Harvard University made seminal observations in support of this thesis. They observed that the placenta of patients with preeclampsia over-expressed the message for an anti-angiogenic protein called soluble Flt-1, or sVEGFR-1 Citation[46], and that this protein was increased in the maternal blood at the time of the diagnosis of disease. Importantly, Maynard et al. Citation[46] demonstrated that transfection of rats with adenoviral vector over-expressing sFlt-1 led to the development of hypertension and proteinuria in the animal, as well as glomerular endotheliosis. This observation published in the Journal of Clinical Investigation accelerated research. Levine et al. Citation[47] and Chaiworapongsa et al. Citation[48] demonstrated that the protein was elevated prior to the onset of clinical disease. Moreover, there was an association between the severity of the disease and the concentration of sFlt-1 Citation[49]. Shortly thereafter, another anti-angiogenic factor, soluble endoglin, was identified to be elevated in patients with preeclampsia at the time of the diagnosis, as well as prior to the development of disease Citation[50-53].
These observations complement a number of studies reported years ago suggesting that a deficiency in placental growth factor (an angiogenic factor) may be observed in patients with preeclampsia and in those with growth-restricted neonates. Therefore, the concept that an imbalance between angiogenic and anti-angiogenic factors may be associated with disease during pregnancy has gained support. However, some questions remain open: (1) What is the behavior of different anti-angiogenic factors and angiogenic factors during the course of normal and pathologic pregnancy? (2) Is an anti-angiogenic state (as defined by the concentrations of these factors) specific to preeclampsia? (3) What is the relationship between the maternal concentration of these factors and complications of pregnancy, with normal and abnormal Doppler? This question is important because abnormal Dopplers of the maternal and/or umbilical circulation could be considered as indicators of deficient vascular biology (umbilical of placental angiogenesis and uterine of maternal vascular state).
These questions are addressed in three articles in the Journal. The first article is a longitudinal study of placental growth factor and two anti-angiogenic factors (soluble Flt-1 and soluble endoglin) in pregnancies with normal outcome, preeclampsia, and SGA Citation[54]. This study suggests that the maternal concentration of placental growth factor behaves differently in preterm and term preeclampsia as well as in SGA. Patients destined to develop preterm preeclampsia have a delayed appearance of placental growth factor in the maternal circulation and reach a lower nadir than normal patients and those who develop preeclampsia at term. Moreover, an increased concentration of soluble Flt-1 was detected in patients destined to develop preeclampsia but not in those who delivered SGA neonates, suggesting a critical role for soluble Flt-1 in the development of preeclampsia. Of interest is that soluble endoglin was elevated from early pregnancy in fetuses destined to be SGA Citation[54].
The relationship between uterine artery and umbilical Doppler velocimetry and the concentration of soluble Flt-1 is described in the second article Citation[55]. The key observations are that the maternal concentration of soluble Flt-1 is higher in patients with SGA when there is an abnormal uterine artery Doppler in comparison to normal pregnancy. In addition, among patients with SGA and those with preeclampsia, the magnitude of the increase in maternal plasma soluble Flt-1 concentrations (delta soluble Flt-1) is related to the presence or absence of Doppler velocimetry abnormalities in the uterine and umbilical arteries Citation[55].
A third article demonstrates that the magnitude of change in the maternal plasma concentrations of anti-angiogenic and angiogenic factors is associated with the subsequent risk for the development of preterm and term preeclampsia as well as delivering an SGA neonate Citation[56].
Is an anti-angiogenic state specific to preeclampsia?
Initial reports have focused largely on preeclampsia Citation[21],Citation[26],Citation[27],Citation[31],Citation[41],Citation[44],Citation[46],Citation[47],Citation[49-51],Citation[57-76]; however, recent studies indicate that an anti-angiogenic state in humans (as determined by the relative concentrations of placental growth factor, soluble Flt-1, and endoglin) is also present in other conditions such as SGA neonates Citation[44],Citation[74],Citation[77-81], mirror syndrome Citation[82-84], placental abruption Citation[85], twin-to-twin transfusion syndrome Citation[86], and fetal death Citation[87]. Several of these observations have been published in the Journal of Maternal-Fetal & Neonatal Medicine and are available via open access. It seems that an anti-angiogenic state is an important mechanism of disease for several complications of pregnancy. It might be that alterations in a specific set of angiogenic and anti-angiogenic factors would result in different phenotypes. The role of genetic predisposition and epigenetic changes is an area ripe for investigation.
Open questions
Much progress has been made in the last five years; however, the following critical questions remain to be answered: (1) Is the determination of angiogenic and anti-angiogenic factors clinically useful to conduct risk assessment for preeclampsia, SGA, placental abruption, etc.? If so, what are the angiogenic and anti-angiogenic factors with prognostic value and when should they be determined? These questions require a large cohort study. (2) Does the combination of angiogenic and anti-angiogenic factor concentration add information to that already provided by uterine artery Doppler velocimetry in the midtrimester of pregnancy? There are already hints that this is the case Citation[88]. (3) Can an anti-angiogenic state in pregnancy be treated with the administration of angiogenic factors?
These exciting questions provide new areas for clinical and basic investigation. The Journal of Maternal-Fetal & Neonatal Medicine is glad to have published many of the seminal observations in this field.
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