Endothelial Barrier Function is co-regulated at Vessel Bifurcations by Fluid Forces and Sphingosine-1-Phosphate

AbstractSphingosine-1-phosphate (S1P) is a blood-borne bioactive lipid mediator of endothelial barrier function. Prior studies have implicated mechanical stimulation due to intravascular laminar shear stress in co-regulating S1P signaling in endothelial cells (ECs). Yet, vascular networks in vivo consist of vessel bifurcations, and this geometry produces hemodynamic forces that are distinct from laminar shear stress. However, the role of these forces at vessel bifurcations in regulating S1P-dependent endothelial barrier function is not known. In this study, we implemented a microfluidic platform that recapitulates the flow dynamics of vessel bifurcations with in situ quantification of the permeability of microvessel analogues. Co-application of S1P with impinging bifurcated fluid flow, which was characterized by approximately zero shear stress and 38 dyn cm-2 stagnation pressure at the vessel bifurcation point, promotes vessel stabilization. Similarly, co-treatment of carrier-free S1P with 3 dyn cm-2 laminar shear stress is also protective of endothelial barrier function. Moreover, it is shown that vessel stabilization due to laminar shear stress, but not bifurcated fluid flow, is dependent on S1P receptor 1 or 2 signaling. Collectively, these findings demonstrate the endothelium-protective function of fluid forces at vessel bifurcations and their involvement in coordinating S1P-dependent regulation of vessel permeability.

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Endothelial Barrier Function is co-regulated at Vessel Bifurcations by Fluid Forces and Sphingosine-1-Phosphate

Biomaterials and Biosystems ◽

10.1016/j.bbiosy.2021.100020 ◽

2021 ◽

pp. 100020

Author(s):

Ehsan Akbari ◽

Griffin B. Spychalski ◽

Miles M. Menyhert ◽

Kaushik K. Rangharajan ◽

Joseph W. Tinapple ◽

...

Keyword(s):

Barrier Function ◽

Endothelial Barrier ◽

Endothelial Barrier Function ◽

Fluid Forces ◽

Sphingosine 1 Phosphate ◽

Vessel Bifurcations

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Competing Fluid Forces Control Endothelial Sprouting in a 3-D Microfluidic Vessel Bifurcation Model

Micromachines ◽

10.3390/mi10070451 ◽

2019 ◽

Vol 10 (7) ◽

pp. 451 ◽

Cited By ~ 8

Author(s):

Ehsan Akbari ◽

Griffin B. Spychalski ◽

Kaushik K. Rangharajan ◽

Shaurya Prakash ◽

Jonathan W. Song

Keyword(s):

Shear Stress ◽

Fluid Flow ◽

Bifurcation Point ◽

Flow Dynamics ◽

Laminar Shear Stress ◽

Local Flow ◽

Fluid Forces ◽

Sprouting Angiogenesis ◽

Laminar Shear

Sprouting angiogenesis—the infiltration and extension of endothelial cells from pre-existing blood vessels—helps orchestrate vascular growth and remodeling. It is now agreed that fluid forces, such as laminar shear stress due to unidirectional flow in straight vessel segments, are important regulators of angiogenesis. However, regulation of angiogenesis by the different flow dynamics that arise due to vessel branching, such as impinging flow stagnation at the base of a bifurcating vessel, are not well understood. Here we used a recently developed 3-D microfluidic model to investigate the role of the flow conditions that occur due to vessel bifurcations on endothelial sprouting. We observed that bifurcating fluid flow located at the vessel bifurcation point suppresses the formation of angiogenic sprouts. Similarly, laminar shear stress at a magnitude of ~3 dyn/cm2 applied in the branched vessels downstream of the bifurcation point, inhibited the formation of angiogenic sprouts. In contrast, co-application of ~1 µm/s average transvascular flow across the endothelial monolayer with laminar shear stress induced the formation of angiogenic sprouts. These results suggest that transvascular flow imparts a competing effect against bifurcating fluid flow and laminar shear stress in regulating endothelial sprouting. To our knowledge, these findings are the first report on the stabilizing role of bifurcating fluid flow on endothelial sprouting. These results also demonstrate the importance of local flow dynamics due to branched vessel geometry in determining the location of sprouting angiogenesis.

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Competing Fluid Forces Control Endothelial Sprouting in a 3-D Microfluidic Vessel Bifurcation Model

10.1101/626531 ◽

2019 ◽

Author(s):

Ehsan Akbari ◽

Griffin B. Spychalski ◽

Kaushik K. Rangharajan ◽

Shaurya Prakash ◽

Jonathan W. Song

Keyword(s):

Shear Stress ◽

Fluid Flow ◽

Bifurcation Point ◽

Flow Dynamics ◽

Laminar Shear Stress ◽

Local Flow ◽

Fluid Forces ◽

Sprouting Angiogenesis ◽

Laminar Shear

AbstractSprouting angiogenesis, the infiltration and extension of endothelial cells from pre-existing blood vessels, helps orchestrate vascular growth and remodeling. It is now agreed that fluid forces, such as laminar shear stress due to unidirectional flow in straight vessel segments, are important regulators of angiogenesis. However, regulation of angiogenesis by the different flow dynamics that arise due to vessel branching, such as impinging flow stagnation at the base of a bifurcating vessel, are not well understood. Here we used a recently developed 3-D microfluidic model to investigate the role of the flow conditions that occur due to vessel bifurcations on endothelial sprouting. We observed that bifurcating fluid flow located at the vessel bifurcation point suppresses the formation of angiogenic sprouts. Similarly, laminar shear stress at a magnitude of ∼3 dyn/cm2 applied in the branched vessels downstream of the bifurcation point, inhibited the formation of angiogenic sprouts. In contrast, co-application of ∼1 µm/s average transvascular flow across the endothelial monolayer with bifurcating fluid flow and laminar shear stress induced the formation of angiogenic sprouts. These results suggest that transvascular flow imparts a competing effect against bifurcating fluid flow and laminar shear stress in regulating endothelial sprouting. To our knowledge, these findings are the first report on the stabilizing role of bifurcating fluid flow on endothelial sprouting. These results also demonstrate the importance of local flow dynamics due to branched vessel geometry in determining the location of sprouting angiogenesis.

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