Trophoblast and knots
Hypoxia (and associated trophoblast damage) is central in current pathophysiological hypotheses of PE42. In PE, trophoblast turnover is no longer balanced. Apoptosis is increased43, differentiation and fusion of the so-called cytotrophoblast to form the syncytium is decreased44, while cytotrophoblast proliferation is reported to be increased or unaltered45-47. Altered trophoblast function provides a potential clarification of observed structural abnormalities in PE (Figure1C and 1D).
Moreover, placental hypoxia has been found to promote the aggregation of syncytial knots 48. Increased syncytial knotting is a clear hallmark of pre-eclamptic placentas13, 35. Distinct 3D conformations (Figures 1E-1H) of knots are potentially related to different pathological mechanisms (i.e., being apoptotic or a mechanism to sequester effete nuclei and create regions for diffusional exchange). Especially WLKs were dominantly present on the investigated EO-PE placenta (Figure 1E). Nonetheless, wave-like apoptotic shedding is not specific for PE and has been described in stem villi from cases with severe IUGR, without PE35, 49. Quantification of knots (shape/volume) could potentially aid in subdivision of pathological, apoptotic, or non-pathological (including sprouts and bridges) knots accordingly. To our knowledge, different shapes of knots have been described50, but quantitative data regarding relative incidences of alternative knot shapes is lacking. Current developed methodology provides an approach to quantitatively investigate knots and their shapes.