Blood vessels develop via two subsequent processes starting with vasculogenesis and subsequently continuing with angiogenesis. During vasculogenesis pluripotent mesenchymal cells differentiate into haemangiogenic stem cells. The latter further differentiate into angioblastic cells that give rise to endothelial precursor cells (Ribatti et al. 2002). At this stage first primitive capillaries are formed. In subsequent stages of differentiation and formation of vessels, new blood vessels derive from already existing vessels, a process called angiogenesis (Hanahan & Folkman 1996). Vasculogenesis and angiogenesis in the human placenta In the very beginning of human placental development, the villous trees are composed of two layer of villous trophoblast and a core of extraembryonic mesenchyme. The process of vasculogenesis is mostly restricted to the period of villous tree formation of placental development while angiogenesis takes place throughout pregnancy until delivery. Vascularisation inside the placenta results from local de-novo development and formation of primitive capillaries from pluripotent mesenchymal cells. Hence within the placenta there is vasculogenesis that is independent from vessel formation inside the embryo; and placental vessels do not result from sprouting of vessels from the embryo into the placenta. At day 21 post conception placental vasculogenesis starts, during the 4 somite embryo stage (Kaufmann et al. 2004; Demir et al. 2005). At this stage, the villous trees comprise primary (only trophoblastic) and secondary (with a mesenchymal core) villi. Within the mesenchymal stroma of secondary villi, haemangiogenic stem cells differentiate, which finally leads to the formation of first vessels. Thus the early placental vessels and their endothelial linings are direct mesenchymal derivatives rather than originating from embryonic blood monocytes. Sequence of events during placental vasculogenesis and angiogenesis The sequence of events during vasculogenesis and angiogenesis in the human placenta (Demir et al. 2004, 2005) can be summarised as follows: (1) Vasculogenesis begins with the differentiation of haemangiogenic stem cells, followed by the formation of vascular patterns. This de novo vessel formation requires a first, so far unknown trigger to induce differentiation of the primary source, pluripotent mesenchymal cell, since already formed endothelia, pre-existing mature endothelial cells or circulating endothelial precursor cells are not available at that time. (2) The first morphological signs of differentiating cells within vascular patterns develop in close vicinity to the villous trophoblast (Demir et al. 2004), which seems to be the major trigger of vasculogenesis (Demir et al. 2004). (3) During ongoing villous maturation vasculogenesis continues while angiogenesis already starts. Now the Hofbauer cells are recruited to further trigger vessel formation (Demir et al. 2004). Depending on the stage of villous maturation VEGF is mostly expressed in villous cytotrophoblasts or Hofbauer cells and fibroblasts (Demir et al. 2004). (4) Primitive vascular tubes are formed by the assembly of several haemangiogenic cells or by differentiation of a single cell to form a primitive lumen (Demir et al. 2004). During this first formation of primitive vascular tubes, differentiating cells come into direct contact with cytotrophoblasts by establishing cytoplasmic projections. (5) With advancing formation and maturation of placental vessels, endothelial progenitor cells show increasing immunoreactivities for CD31 and CD34, while further differentiated haematopoietic cells do not show any immunoreactivity for these proteins. (6) Further processes of developmental and differentiation continue leading to the generation of endothelial cells and also first perivascular cell populations. This development of perivascular sheets including a muscular layer to form contractile vessels is induced by growth factors and cytokines derived from the local villous environment as well as from the already established foetal circulation. In summary, placental vasculogenesis starts with the differentiation of pluripotent mesenchymal cells into first primitive vessels. Then angiogenesis takes over leading to the formation of further primitive as well as mature vessels. Only at these later stages embryonic cells participate in placental vessel development, which starts independent from the embryo inside the human placenta.