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

Win M Tun,Shier Nee Saw,Choon Hwai Yap,Joanna L James,Alys R Clark

doi:10.1038/s41598-019-46151-6

Win M Tun, Shier Nee Saw + Show 3 more

Open Access

https://doi.org/10.1038/s41598-019-46151-6

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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.

Highlights

Fetal growth restriction (FGR), a pregnancy complication where the fetus fails to meet its genetically determined growth potential, is frequently linked to placental dysfunction[1]
To understand the relationship between shear stress and blood vessel development in FGR, we simulate the distribution of flow and shear stress in the normal and FGR placental vasculatures (Fig. 1)
Our model predicts an increase in volumetric blood flow per capillary in FGR placentae: 0.22 μl/min, 0.31 μl/min and 0.40 μl/min compared to 0.13 μl/min in normal placentae

Summary

Introduction

Fetal growth restriction (FGR), a pregnancy complication where the fetus fails to meet its genetically determined growth potential, is frequently linked to placental dysfunction[1]. The placenta is an essential organ for a successful pregnancy since it provides the oxygen and nutrients required for normal fetal growth It plays critical roles in adapting the maternal uterine circulation to increase delivery of nutrient-rich maternal blood to its surface, and in absorbing the nutrients from this blood efficiently[3]. Placental vascular development is regulated by a complex network of paracrine factors including vascular endothelial growth factor (VEGF), placental growth factor (PlGF), angiopoietin 1 and 2 (Ang 1&2), fibroblast growth factor (FGF) and platelet derived growth factor (PDGF)[16,17] Levels of these growth factors are impaired in FGR placentae, and this is thought to contribute to the poor vascular development seen in FGR17. We have no understanding of how shear stress may affect placental vascular malformation in FGR, or how the structural differences we see in the vasculature of FGR placentae may impact shear stress in those vessels

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