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

Abstract

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.

Micro-strains in the extracellular matrix induce angiogenesis

“…[28][29][30][31][32][33][34][35][36][37][38][39][40][41] Forces due to increased interstitial flow from "leaky" tumor blood vessels can also drive tumor progression, through integrins or growth factor receptors. 35,[42][43][44][45][46][47][48][49] Elucidating how biomechanical properties of CAFs affect tumor angiogenesis requires advanced in vitro models that permit isolation of biomechanical and biochemical factors.…”

Blood Flow Forces in Shaping the Vascular System: A Focus on Endothelial Cell Behavior

“…Once again, the response is dependent on the flow profile ECs experience. For example, flow-derived forces can compete to regulate angiogenic sprouting and sometimes have opposite effects on sprouting location (Akbari et al, 2019). Sprout formation is supressed by impinging flow stagnation or by laminar shear stress, at the bifurcation point or downstream of it, respectively, while combined application of transvascular and intraluminar flow promotes angiogenic sprouting (Akbari et al, 2019).…”

Fluid flow as a driver of embryonic morphogenesis

“…Although VEGF initiates sprouting, VEGF distribution is not simply defined by passive diffusion, but is determined by interstitial flow (Ghaffari et al, 2017). Increased interstitial flow in the direction of sprouting enhances sprouting and sprout extension follows the interstitial flow patterns (Akbari et al, 2019;Ghaffari et al, 2017;Kim et al, 2016). Furthermore, sprout elongation follows the interstitial flow patterns and the speed of elongation is proportional to the magnitude of interstitial flow (Ghaffari et al, 2017).…”