Current OpinionSequential Steps During Vasculogenesis and Angiogenesis in the Very Early Human Placenta
Introduction
It is generally accepted that blood vessels develop via two subsequent processes. During vasculogenesis, formation of the earliest primitive capillaries is achieved by in situ differentiation of hemangiogenic stem cells that are derived from pluripotent mesenchymal cells. The resulting angioblastic cells give rise to endothelial precursor cells [1] (Figure 1). Only thereafter, during angiogenesis new blood vessels derive from already existing vessels [2].
Physiological as well as pathological processes require vasculogenesis and angiogenesis for the same reason, blood supply. Different inducers and stimulators affect angiogenesis and vasculogenesis by directly or indirectly stimulating proliferation, differentiation and migration of endothelial or respective precursor cells [2], [3].
Here, we aim to highlight the chronological steps and consequences of stromal cell differentiation in the placental villous core regarding vasculogenesis and angiogenesis including the action of cytotrophoblast and placental macrophages (Hofbauer cells), known triggers of both processes. Recently, we have analyzed these processes by studying the temporal and spatial expression of VEGF, VEGFR-1 and VEGFR-2, angiopoietin receptors, Tie-1 and Tie-2 in relation to the vascular maturation in the human placenta [4], [5]. We have shown that a variety of factors are associated with placental angiogenesis and vasculogenesis. Taking our and other data, this current opinion will describe our view on placental vasculogenesis and angiogenesis early in pregnancy.
Section snippets
VEGF and its receptors during placental vasculogenesis
The vascular endothelial growth factors (VEGFs) [6] belong to the main factors of vasculogenesis and angiogenesis [7]. VEGF directly binds to its surface receptors VEGFR-1 (Flt-1) and VEGFR-2 (Flk-1/KDR) that have been shown to be type III receptor tyrosine kinases [8]. The recently identified angiopoietin receptors, Tie-1 and Tie-2 are also a class of receptor tyrosine kinases that are related to the formation of blood vessels [9]. VEGFR-1 also binds the placenta growth factor (PlGF) [10] a
Sequential steps during placental vasculogenesis and angiogenesis
We want to highlight the emerging importance of the sequential steps during vasculogenesis and angiogenesis early in placentation [4], [22]:
- (I)
Vasculogenesis begins with the formation of hemangiogenic stem cells before the formation of vessels takes place, thus the main stem cells of placental vasculogenesis are pluripotent mesenchymal cells (Figure 1). During this de novo vessel formation, there is the need for a first trigger to induce differentiation of the primary source cells, pluripotent
The microenvironment and vessel formation – a hypothesis
The hemangiogenic stem cells are able to differentiate into two diverse branches of further differentiating cells, a series of hematopoietic cells and a series of angioblastic cells giving rise to vascular endothelial cells [24]. Distinct hematopoietic and angioblastic cells can be seen around day 21 post-conception of human pregnancy. The vascular endothelial growth factor receptor, VEGFR-2, is also expressed at that time [4], most likely by hemangiogenic cells [25], [26].
In the development of
Conclusion
By combining our data with those from the literature, we were able to refine the order of developmental stages of placental vasculogenesis and angiogenesis during very early placental development. Placental vasculogenesis starts with differentiation of pluripotent mesenchymal cells. The following hemangiogenic stem cells with further daughter cell populations can be seen as successive steps of angiogenic cell differentiation.
Acknowledgment
This study was supported in part by The Research Fund of Akdeniz University, Antalya, Turkey.
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