Regulation of placental angiogenesis

Abstract

Ample interest has been evoked in using placental angiogenesis as a target for the development of diagnosis tools and potential therapeutics for pregnancy complications based on the knowledge of placental angiogenesis in normal and aberrant pregnancies. Although these goals are still far from reach, one would expect that two complementary processes should be balanced for therapeutic angiogenesis to be successful in restoring a mature and functional vascular network in the placenta in any pregnancy complication: (i) pro-angiogenic stimulation of new vessel growth and (ii) anti-angiogenic inhibition of vessel overgrowth. As the best model of physiological angiogenesis, investigations of placental angiogenesis provide critical insights not only for better understanding of normal placental endothelial biology but also for the development of diagnosis tools for pregnancy complications. Such investigations will potentially identify novel pro-angiogenic factors for therapeutic intervention for tissue damage in various obstetric complications or heart failure or anti-angiogenic factors to target on cancer or vision loss in which circulation needs to be constrained. This review summarizes the genetic and molecular aspects of normal placental angiogenesis as well as the signaling mechanisms by which the dominant angiogenic factor vascular endothelial growth factor regulates placental angiogenesis with a focus on placental endothelial cells.

Keywords: VEGF; angiogenesis; placenta; signaling; transcription.

Fig. 1. Sequential regulation of placental vasculogenesis and angiogenesis during human placental development

Vascular endothelial growth factor (VEGF) is critically important for both placental vasculogenesis and angiogenesis throughout gestation, while fibroblast growth factor (FGF2) and VEGF are important for the formation of angioblasts along with the formation of the first mesenchymal villi. VEGF and placental growth factor (PlGF) are critically important for the formation of placental capillary network via sprouting and elongation with the development of the villous tree. Angiopoietins and many other growth factors are upregulated to facilitate the expansion of placental vascular network during the third trimester.

Fig. 2. Signaling control of vascular endothelial growth factor (VEGF)-induced placental endothelial angiogenesis

VEGF promotes placental endothelial proliferation, migration and tube formation via the activation of a complex signaling network involving the MAPK, PI3K/Akt1, and eNOS-NO pathways.