Angiogenesis and villous development in human placenta

Abstract

Fetal well being requires adequate growth and maturation of placental villous trees. During gestation new phenotypes and relationships appear: precursor villi produce stem villi (the tree trunks), terminal villi (the finest branches) and intermediate forms called immature and mature intermediate villi (IIV and MIV). Before about 20 week, the emphasis is on producing IIV and stem villi. Thereafter production switches from IIV to MIV and from these abundant terminal villi are generated. The switch depends on fetal vascular development influenced by local O2 tensions, growth factor receptors and their ligands (notably vascular endothelial growth factor, VEGF, and placental growth factor, PlGF). From 9 to 25 week (low O2 tensions, high VEGF levels) fetal capillaries grow by branching angiogenesis. Between 15 and 32 week (high O2 tensions, low VEGF, high PlGF levels) they grow via nonbranching angiogenesis (linear growth of existing capillaries). Quantitative measures of these differences have been made using indices of villous and vessel growth (volumes, surfaces, lengths; numbers of endothelial cells) coupled with estimators of vessel calibre (mean cross sectional area) and endothelial cell size (squame surface area). Estimates were obtained stereologically using randomly sampled histological wax sections of placentas from 10 to 41 week. Here the following definitions apply: the term TV embraces true terminal villi plus some of the thinner MIV, intermediate villus (IV) includes IIV and MIV, whilst stem villus includes stem villi and larger IIV. Results were analysed by regression analysis and analysis of variance on untransformed or log transformed data. From 10 week, all villous compartments grew but the volume of capillaries expanded disproportionately to stroma and trophoblast. Capillary growth was proliferative and essentially linear (i.e. not due to increases in calibre). The volume of TV altered dramatically but the increase in IV volume was modest and the volume of stem villi did not alter significantly. During villous growth TV and IV became longer and thinner with larger surface areas. For most variables gestational changes showed inflection points at 20–25 week and growth was faster after the inflection point. Exceptionally, IV volume increased up to 24 week but not thereafter. In addition capillary to villus length ratios displayed 2 growth phases: the first (peaking before 20 week) was followed by a sharp drop preceding gradual restoration of peak values by term. In the first phase the mean area of an endothelial squame was maintained but squame size increased during the second phase. These findings confirm and extend the spatiotemporal patterns of change identified by qualitative studies and are consistent with branching and nonbranching angiogenesis being important phases in villous development.