Wall shear stress gradients (WSSGs) induce an inflammatory phenotype in endothelial cells (ECs) which is hypothesized to be mediated by mechanotransduction through the EC glycocalyx (GCX). We used a three-dimensional in vitro cell culture model with a 180o curved geometry to investigate if WSSGs created by curvature can cause EC inflammation and disruption of the GCX. The hydrodynamics of the model elicited a morphological response in ECs as well as a pattern of leukocyte adhesion towards the inner wall of curvature that was attenuated with enzymatic removal of GCX components. GCX degradation was also observed in regions of curvature which corresponded to increased activity of MMPs. Together, these results support the hypothesis that the EC GCX is involved in mechanotransduction of WSSGs and that components of the GCX are regulated by MMP activity in regions of curvature.

/pdf/increased-mmp-activity-in-curved-geometries-disrupts-the-2sjchuoyh7.pdf

Increased MMP activity in curved geometries disrupts the endothelial cell glycocalyx creating a proinflammatory environment

Red blood cell (RBC) disorders affect billions worldwide. While alterations in the physical properties of aberrant RBCs and associated hemodynamic changes are readily observed, in conditions such as sickle cell disease and iron deficiency, RBC disorders can also be associated with vascular dysfunction. The mechanisms of vasculopathy in those diseases remain unclear and scant research has explored whether biophysical alterations of RBCs can directly affect vascular function. Here we hypothesize that the purely physical interactions between aberrant RBCs and endothelial cells, due to the margination of stiff aberrant RBCs, play a key role in this phenomenon for a range of disorders. This hypothesis is tested by direct simulations of a cellular scale computational model of blood flow in sickle cell disease, iron deficiency anemia, COVID-19, and spherocytosis. We characterize cell distributions for normal and aberrant RBC mixtures in straight and curved tubes, the latter to address issues of geometric complexity that arise in the microcirculation. In all cases aberrant RBCs strongly localize near the vessel walls (margination) due to contrasts in cell size, shape, and deformability from the normal cells. In the curved channel, the distribution of marginated cells is very heterogeneous, indicating a key role for vascular geometry. Finally, we characterize the shear stresses on the vessel walls; consistent with our hypothesis, the marginated aberrant cells generate large transient stress fluctuations due to the high velocity gradients induced by their near-wall motions. The anomalous stress fluctuations experienced by endothelial cells may be responsible for the observed vascular inflammation. Significance Statement A common and potentially life-threatening complication of blood cell disorders is inflammation and dysfunction of the vascular wall, for reasons that remain unclear. To address this issue, we explore a purely biophysical hypothesis involving red blood cells using detailed computational simulations. Our results show that red blood cells that are pathologically altered in cell shape, size, and stiffness, which occurs in various blood disorders, strongly marginate, residing primarily in the cell-free layer near blood vessel walls, generating large shear stress fluctuations at the vessel wall that may be responsible for endothelial damage and inflammation.

/pdf/marginated-aberrant-red-blood-cells-induce-pathologic-2vqfglo1.pdf

Marginated aberrant red blood cells induce pathologic vascular stress fluctuations in a computational model of hematologic disorders

An investigation of red blood cells (RBCs) margination’s dependence on channel cross-section shape is presented. The irregularity of the vascular cross-section has been proved to satisfy the condition for stiffened RBCs to perform margination in vivo, while the effect of channel geometry along channel width on cell margination has not been revealed. To illustrate this problem, RBCs’ flowing behaviors in three different microchannels with cross-section of circular, rectangular and irregular are investigated, the forces acted on normal and stiffened RBCs are analyzed and calculated, the motions of RBCs are simulated, and the combined effect of channel geometry and fluid property is demonstrated. The stiffened RBCs are found to perform margination in rectangular and irregular channel with viscoelastic fluid, while not in circular channel under the same fluid condition. Furthermore, the importance of fluid viscoelasticity to cell margination is demonstrated in different microchannel. Our findings might offer some new insights to design microfluidic devices for cell-sorting technology and drug delivery system with high efficiency.

Margination mechanism of stiffened red blood cell in microchannel with different cross-section shapes

Red blood cell (RBC) disorders such as sickle cell disease affect billions worldwide. While much attention focuses on altered properties of aberrant RBCs and corresponding hemodynamic changes, RBC disorders are also associated with vascular dysfunction, whose origin remains unclear and which provoke severe consequences including stroke. Little research has explored whether biophysical alterations of RBCs affect vascular function. We use a detailed computational model of blood that enables characterization of cell distributions and vascular stresses in blood disorders and compare simulation results with experimental observations. Aberrant RBCs, with their smaller size and higher stiffness, concentrate near vessel walls (marginate) because of contrasts in physical properties relative to normal cells. In a curved channel exemplifying the geometric complexity of the microcirculation, these cells distribute heterogeneously, indicating the importance of geometry. Marginated cells generate large transient stress fluctuations on vessel walls, indicating a mechanism for the observed vascular inflammation.

Vessel Geometry Interacts with Red Blood Cell Stiffness to Promote Endothelial Dysfunction in Sickle Cell Disease

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Vessel Geometry Interacts with Red Blood Cell Stiffness to Promote Endothelial Dysfunction in Sickle Cell Disease