Endothelial phenotype of the materno–fetal barrier

The terminal villous capillaries of the human placenta are the sites of maximal materno‐fetal exchange. These capillaries are highly angiogenic and are formed in the last trimester of pregnancy by looped angiogenesis from existing microvessels in the intermediate villi. They represent an ‘activated’ phenotype by possessing adherens junctions which contain VE‐cadherin (– and (– catenin but lack plakoglobin, the component of well differentiated junctions. The tight junctions present here show negative immunoreactivity to occludin and claudin‐1. The conduit vessels further upstream in the stem villi have the full complement of adherens and tight junctional molecules. VEGF and angiopoietin‐2 is present in terminal villi whilst angiopoietin‐1 appears to be a predominant feature of stem villi. The phenotype of junctions present in nascent vessels of the first trimester placentae was similar to the angiogenic terminal villous capillaries. The predominant growth factor here was VEGF, localised to all villi. Isolation of endothelial cells from last trimester placenta microvessels (HPMEC) demonstrated that these cells are capable of differential expression and dynamic regulation of cell‐cell junctions. Cells grown in the presence of ECGS showed a reduction in the level and junctional localisation of plakoglobin and occludin, with associated increased permeability to macromolecules. These adhesion molecules were up‐regulated and targeted back to cell‐cell contact regions by growing HPMEC in the presence of cAMP enhancing agents. This resulted in a 1.7 times increase in transendothelial resistance whilst proliferation of HPMEC cells was inhibited by elevated cAMP. HUVEC cells isolated from the umbilical cords of these placentae contain the full repertoire of AJ molecules in normal culture conditions with no change in composition or resistance under elevated cAMP. The differential expression of junctional adhesion molecules along the placental vascular tree and their in vitro plasticity suggests there is a physiological relevance of junctional regulation in the placenta. The activated junctional phenotype of the newly formed terminal microvessels allows them to participate in increased growth, proliferation and solute exchange in the last trimester when fetal demand is at its greatest. Furthemore, this necessary junctional immaturity of new/angiogenic human vessels appear to be at the expense of barrier function. Funded by the Wellcome Trust.