Balance of interstitial flow magnitude and vascular endothelial growth factor concentration modulates three-dimensional microvascular network formation

Abstract

Hemodynamic and biochemical factors play important roles in critical steps of angiogenesis. In particular, interstitial flow has attracted attention as an important hemodynamic factor controlling the angiogenic process. Here, we applied a wide range of interstitial flow magnitudes to an in vitro three-dimensional (3D) angiogenesis model in a microfluidic device. This study aimed to investigate the effect of interstitial flow magnitude in combination with the vascular endothelial growth factor (VEGF) concentration on 3D microvascular network formation. Human umbilical vein endothelial cells (HUVECs) were cultured in a series of interstitial flow generated by 2, 8, and 25 mmH 2 O. Our findings indicated that interstitial flow significantly enhanced vascular sprout formation, network extension, and the development of branching networks in a magnitude-dependent manner. Furthermore, we demonstrated that the proangiogenic effect of interstitial flow application could not be substituted by the increased VEGF concentration. In addition, we found that HUVECs near vascular sprouts significantly elongated in >8 mmH 2 O conditions, while activation of Src was detected even in 2 mmH 2 O conditions. Our results suggest that the balance between the interstitial flow magnitude and the VEGF concentration plays an important role in the regulation of 3D microvascular network formation in vitro .

Micro-strains in the extracellular matrix induce angiogenesis

“…Recent studies from Abe et al demonstrate the crosstalk of VEGF signaling and interstitial flow, highlighting how these factors interact and affect angiogenesis. 58 Previous work in our lab generated microtissues with self-assembled vascular networks composed of endothelial colony forming endothelial cells and a stromal cell. 43,51,52,[59][60][61] The objective of the current study was to develop and optimize a multi-tissue chamber model with independent control over multiple mechanical factors to investigate angiogenesis associated with tumor progression.…”

In vitro 3D Systems to Model Tumor Angiogenesis and Interactions With Stromal Cells

“…This microfluidic device incorporates features such as: (i) contact between the abluminal side of EC and the hydrogel to allow angiogenic sprouting; (ii) fluid flowing through two adjacent channels and controllable fluid convection through the hydrogel; (iii) co-culture with other cell types seeded either in the central hydrogel or in the opposite channel to EC; (iv) specific growth factors gradients. This microfluidic platform has given rise to many proximate designs that are now commonly used by many research groups (Yeon et al, 2012;Abe et al, 2019;van Duinen et al, 2019).…”

“…There is a distinction between the functional perfusion of the entire microvascular networks (Kim et al, 2013;van Duinen et al, 2019) and interstitial flow applied in the microfluidic device without perfused capillaries (Abe et al, 2019). Microfluidic devices allow investigation of specific mechanical factors consisting in forces generated by fluid flow through either the hydrogel or the microvascular network, respectively, mimicking the interstitial (Abe et al, 2019) and the blood flow (Jeon et al, 2015). For example, in the single gel channel device of Song and Munn (2011) described above, convective flow through media channels results in interstitial flow across the hydrogel region.…”

“…However, it remains unclear whether interstitial flow magnitude can be optimized to control 3D vascular network formation in combination with various VEGF concentrations. Therefore, using a wide range of interstitial flow in a microfluidic device dedicated to angiogenesis, Abe et al (2019) demonstrated a pro-angiogenic effect of the interstitial flow that is not substituted by increasing VEGF concentration. Indeed, density and length of the microvascular network as well as lumen diameter of capillaries and area of degraded gel increased specifically in response to flow magnitude.…”

Microphysiological systems

“…Abe et al 5 investigate the balance between biochemical factors that induce angiogenesis and an alternative approach in which transmural flow takes place across the monolayer from the cell-extracellular matrix (ECM) into the open lumen. They find that, interestingly, either biochemical or mechanical stimuli can produce similar levels of angiogenic sprouting from an endothelial monolayer.…”