Differences in placental capillary shear stress in fetal growth restriction may affect endothelial cell function and vascular network formation

Abstract

Fetal growth restriction (FGR) affects 5-10% of pregnancies, leading to clinically significant fetal morbidity and mortality. FGR placentae frequently exhibit poor vascular branching, but the mechanisms driving this are poorly understood. We hypothesize that vascular structural malformation at the organ level alters microvascular shear stress, impairing angiogenesis. A computational model of placental vasculature predicted elevated placental micro-vascular shear stress in FGR placentae (0.2 Pa in severe FGR vs 0.05 Pa in normal placentae). Endothelial cells cultured under predicted FGR shear stresses migrated significantly slower and with greater persistence than in shear stresses predicted in normal placentae. These cell behaviors suggest a dominance of vessel elongation over branching. Taken together, these results suggest (1) poor vascular development increases vessel shear stress, (2) increased shear stress induces cell behaviors that impair capillary branching angiogenesis, and (3) impaired branching angiogenesis continues to drive elevated shear stress, jeopardizing further vascular formation. Inadequate vascular branching early in gestation could kick off this cyclic loop and continue to negatively impact placental angiogenesis throughout gestation.

Figure 1

(a) A schematic diagram illustrating computational model generation for pre-capillary placental vascular branches. The placental volume is seeded with a fixed density of points, and tree structures are grown toward these points. Sparser seed points result in a sparser vascular tree. (b) A schematic diagram of capillary loops that reside distal to intermediate villi and are simplified in the model as a lumped structure. In normal placentae capillary branching is denser than that in FGR placenta.

Figure 2

Side (a,c) and top (b,d) views of the normal and FGR placental models (pre-capillary level). Normal placentae have an abundant vascular network, whereas FGR placentae are smaller with a sparser vascular network. (e) Box and whisker plot showing the median, range and interquartile range of predicted placental capillary shear stress from normal and FGR models. Outlier data points are identified as gray crosses (‘+’).

Figure 3

Bar graphs showing the mean migration speed of HUVECs (a) and HMEC-1 (b) under shear stress of normal (0.05 Pa) and FGR conditions (0.1, 0.15 and 0.2 Pa). Error bars represent the standard error (* and ** show statistical significance, *p = 0.01, **p < 0.0001). Line graphs showing the persistency of HUVECs (no significant differences) (c) and HMEC-1 (0.05 Pa and 0.1 Pa are significantly less persistent than 0.15 and 0.2 Pa, p < 0.001) (d) under shear stress. Bar graphs showing the proportion of HUVECs (e) and HMEC-1 (f) that incorporated BrdU over a 4 hr period.