Disrupted Balance of Angiogenic and Antiangiogenic Signalings in Preeclampsia

Abstract

The placenta plays a central role in governing local circulatory system that mediates maternal condition and fetal growth. In early gestational phases, the placenta exerts properties of invasion and neovascularization for successful placentation. Extravillous invasive trophoblasts replace uterine endometrial vasculature and establish local blood pathway to obtain oxygen and nutrients from the mother. In later phases, the placenta promotes villous angiogenesis and vascular maturation that are finely controlled by angiogenic and antiangiogenic molecules. Among various molecules involved in placental neovascularization, vascular endothelial growth factor receptors (VEGFRs) and angiotensin II receptor type 1 (AT1) mediate important signaling pathways for maternal circulatory system and fetal growth. VEGFR1 and VEGFR2 are functional receptors for placental growth factor (PlGF) and VEGF, respectively, and PlGF-VEGFR1 and VEGF-VEGFR2 interactions are disturbed in many preeclamptic patients by excess amount of soluble form of VEGFR1 (also named sFlt1), a natural PlGF/VEGF antagonist. Recent studies have disclosed that excessive sFlt1 production in the placenta and aberrant AT1 signaling in the mother are closely associated with the pathology of preeclampsia and intrauterine growth restriction (IUGR). In this paper, neovascularization of the placenta and pathological events associated with disrupted balance between angiogenic and antiangiogenic signaling in preeclampsia are discussed.

PlGF: A Multitasking Cytokine with Disease-Restricted Activity

“…This effect is particularly pronounced in uterine arteries during pregnancy, suggesting that PlGF contributes to uterine vascular remodeling during pregnancy (Osol et al 2008). These findings are consistent with data that utero-placental hypoperfusion and hypertension in preeclampsia patients reduce PlGF plasma levels, because of excessive release of sFLT1, causing endothelial dysfunction in maternal tissue (Foidart et al 2009;Furuya et al 2011). Whether PlGF delivery offers novel therapeutic opportunities for preecclampsia remains to be determined.…”

“…However, high sFLT1 levels in the placenta likely neutralize local PlGF (Kendall et al 1996;Cindrova-Davies et al 2011;Furuya et al 2011). PlGF also regulates the maturation of uterine natural killer cells in the endometrium needed for trophoblast invasion (Tayade et al 2007).…”

Levels of Maternal Serum Angiogenic Factors in Third-Trimester Normal Pregnancies: Reference Ranges, Influence of Maternal and Pregnancy Factors and Fetoplacental Doppler Indices

“…The secretion and biological activity of PlGF is highly regulated through secretion as a homodimer (PlGF:PlGF) or heterodimer (PlGF:VEGF-A), and regulation of its receptor signaling achieved by the presence of a soluble form of its receptor (sVEGFR-1, also named sFlt-1) in the circulation, which neutralizes local PlGF [31,32]. Interestingly, we found correlations, albeit weaker, between fetomaternal Doppler parameters and angiogenic factors.…”

Preeclampsia, prematurity and cardiovascular health in adult life

“…This leads to the release of reactive oxygen species that trigger a systemic oxidative and inflammatory state [27]. As such, offspring of preeclamptic pregnancies develop in an environment of placental insufficiency, restricted oxygen supply [28] and abnormal levels of circulating antiangiogenic factors in the mother [29]. Animal studies indicate exposure to hypoxia related to abnormal placental development results in elevated myocardial collagen [30].…”