Role of the fetoplacental endothelium in fetal growth restriction with abnormal umbilical artery Doppler velocimetry

Abstract

Growth-restricted fetuses with absent or reversed end-diastolic velocities in the umbilical artery are at substantially increased risk for adverse perinatal and long-term outcome, even in comparison to growth-restricted fetuses with preserved end-diastolic velocities. Translational studies show that this Doppler velocimetry correlates with fetoplacental blood flow, with absent or reversed end-diastolic velocities signifying abnormally elevated resistance within the placental vasculature. The fetoplacental vasculature is unique in that it is not subject to autonomic regulation, unlike other vascular beds. Instead, humoral mediators, many of which are synthesized by local endothelial cells, regulate placental vascular resistance. Existing data demonstrate that in growth-restricted pregnancies complicated by absent or reversed umbilical artery end-diastolic velocities, an imbalance in production of these vasoactive substances occurs, favoring vasoconstriction. Morphologically, placentas from these pregnancies also demonstrate impaired angiogenesis, whereby vessels within the terminal villi are sparsely branched, abnormally thin, and elongated. This structural deviation from normal placental angiogenesis restricts blood flow and further contributes to elevated fetoplacental vascular resistance. Although considerable work has been done in the field of fetoplacental vascular development and function, much remains unknown about the mechanisms underlying impaired development and function of the human fetoplacental vasculature, especially in the context of severe fetal growth restriction with absent or reversed umbilical artery end-diastolic velocities. Fetoplacental endothelial cells are key regulators of angiogenesis and vasomotor tone. A thorough understanding of their role in placental vascular biology carries the significant potential of discovering clinically relevant and innovative approaches to prevention and treatment of fetal growth restriction with compromised umbilical artery end-diastolic velocities.

Keywords: VGEF; VGEF receptor 2; absent end-diastolic velocity; angiogenesis; fetal growth restriction; fetoplacental endothelium; placental circulation; placental growth factor; umbilical artery Doppler.

Conflict of interest statement

Disclosures: The author reports no conflict of interest

Copyright © 2015 Elsevier Inc. All rights reserved.

Figures

Figure 1. Fetoplacental villous development throughout pregnancy

(I) In post-menstrual (p.m.) weeks 5–6, fetal capillary segments are formed by vasculogenesis within mesenchymal villi (mv). (II) These fuse to form a simple capillary bed in weeks 7–8. (III) Between 9–25 weeks, this capillary bed expands by angiogenesis as mesenchymal villi develop into immature intermediate villi (iiv). (IV) Immature intermediate villi become transformed into stem villi (sv), while peripheral mesenchymal villi are transformed into mature intermediate villi (miv) between weeks 15–32. Concomitantly, centrally located capillaries develop into stem villous vessels, and the peripheral vasculature elongates. (V) In the last half of pregnancy, there is continued angiogenesis as terminal villi (tv) develop, resulting in the villous morphology demonstrated inVb. In placentas from FGR pregnancies with preserved end-diastolic velocities, villi either resemble that illustrated in Vb or Vc, whereas FGR pregnancies complicated by AEDV/REDV have villi similar to that depicted inVa. (Blue: Endothelial tubes; Brown: Vascular smooth muscle cells; Green: Collagen fibers). From: Benirschke K, Burton GJ, Baergen RN. Architecture of normal villous trees. In: Pathology of the human placenta. New York, NY: Springer-Verlag Berlin Heidelberg; 2012: 122. With permission from Dr. Kurt Benirschke, Dr. Graham Burton, and Dr. Rebecca Baergen in addition to Springer Science + Business Media.