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.

Angiogenesis in Tissue Engineering: As Nature Intended?

“…The endothelial layer of blood vessels is constantly exposed to the blood stream and hemodynamic forces, such as shear stress and tangential forces (Song and Munn, 2011). Cells respond to these forces by changing their morphology and gene expression (Wragg et al, 2014), with shear stress inhibiting EC proliferation and limiting sprouting to low flow regions (e.g., tumor microenvironment and ischemia) (Song and Munn, 2011;Tun et al, 2019). Song and Munn (2011) developed a perfused microfluidic device and reported a reduction in VEGFinduced sprouting under physiological shear stress.…”

A new microfluidic model that allows monitoring of complex vascular structures and cell interactions in a 3D biological matrix

“…91 For example, the shear stress in glomerular capillaries ranges between 1 and 95 dyne per cm 2 , 92 whereas shear stress in the capillaries of the highly vascularized placenta is calculated to be ∼0.5 dyne per cm 2 . 93 Furthermore, shear stress is often calculated based on the following equation: τ w = 4μQ/πr3, in which shear stress at the luminal wall (τ w ) depends on flow rate (Q), fluid viscosity (μ), and inner radius the vessel (r). It has been suggested that although this is a correct assumption for larger straight vessels segments with limited bifurcations, an alternative formula should be used to calculated wall shear stress in capillaries of the microvascular bed: τ w = ΔPd/4L, with wall shear stress (τ w ) calculated from the pressure difference across the capillary (ΔP), and the inner diameter (d) and length (L) of the capillary.…”

Computational modeling of the interactions between the maternal and fetal circulations in human pregnancy

“…Top : shows computational models that aim to predict function at scales reflective of the images below them. Left to right : (a) Gill et al (2011) predicted nutrient concentration in villous structures (reproduced with permission), (b) model of shear stress over terminal villi (reproduced under Creative Commons Attribution License, Lecarpentier et al (2016)), (c) a model of the branching structure of feto‐placental vasculature (Clark et al, 2015; Tun et al, 2019), (d) predictions of velocity streamlines in a porous media model of IVS blood flow with local permeability a function of villous tree structure (Lin et al, 2016), (e) an illustration of the typical structure of transmission line models often used to predict Doppler waveforms. Bottom : shows a range of uteroplacental imaging technologies.…”

“…This suggested a possible mechanism for the longer, thinner vessels seen in FGR, as random rather than persistent (with flow) endothelial motility is required for effective branching angiogenesis. If this is the case, then it is likely that the pathophysiology of FGR could be self‐perpetuating, with longer, thinner vessels leading to increased shear stress, further decreasing random migration/vessel branching and promoting the growth of long and thin vessels (Tun et al, 2019). Remarkably, despite being a key developmental process there are few computational models of cell behaviors within the placenta or of placental vasculogenesis or angiogenesis.…”