Abstract
Extravasation of circulating cells is an essential process that governs tissue inflammation and the body's response to pathogenic infection. To initiate anti-inflammatory and phagocytic functions within tissues, immune cells must cross the vascular endothelial barrier from the vessel lumen to the subluminal extracellular matrix. In this work, we present a microfluidic approach that enables the recreation of a three-dimensional, perfused endothelial vessel formed by human endothelial cells embedded within a collagen-rich matrix. Monocytes are introduced into the vessel perfusate, and we investigate the role of luminal flow and collagen concentration on extravasation. In vessels conditioned with the flow, increased monocyte adhesion to the vascular wall was observed, though fewer monocytes extravasated to the collagen hydrogel. Our results suggest that the lower rates of extravasation are due to the increased vessel integrity and reduced permeability of the endothelial monolayer. We further demonstrate that vascular permeability is a function of collagen hydrogel mass concentration, with increased collagen concentrations leading to elevated vascular permeability and increased extravasation. Collectively, our results demonstrate that extravasation of monocytes is highly regulated by the structural integrity of the endothelial monolayer. The microfluidic approach developed here allows for the dissection of the relative contributions of these cues to further understand the key governing processes that regulate circulating cell extravasation and inflammation.
Highlights
Extravasation is the process by which cells and proteins traverse the endothelial barrier from the intravascular cannula into surrounding tissue.[1]
This model system improves upon traditional assays by allowing for modulation of key hemodynamic scitation.org/journal/bmf parameters, including pressure and flow, for vessels embedded within a three-dimensional extracellular matrix with varying density
We demonstrate that both flow and matrix density play key roles in adhesion, extravasation, and migration, and, interestingly, our data demonstrate a complex interplay among biophysical parameters that govern monocyte–endothelial interactions
Summary
Extravasation is the process by which cells and proteins traverse the endothelial barrier from the intravascular cannula into surrounding tissue.[1]. Immune cells from damaged tissue secrete inflammatory cytokines induce the expression of adhesion molecules in endothelial cells. E- and P-selectin, intercellular adhesion molecule 1 (ICAM-1), and vascular cell adhesion molecule 1 (VCAM-1) have been implicated in monocyte–endothelial interactions.[5] ICAM-1 and VCAM-1 contribute to monocyte adhesion,[6] and VCAM-1 reduces rolling speed and enhances firm arrest.[7] monocytes have basal expression of P-selectin Glycoprotein Ligand 1 (PSGL-1), which interacts with endothelial selectins, allowing for the attachment and rolling of monocytes.[8] Once monocytes attach to the endothelial wall, an increase in endothelial RhoA GTPase-mediated actomyosin contractility in endothelial cells induces intercellular junction disassembly and the formation of transient gaps in the monolayer.[9]
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