Cell organization is largely orchestrated by extracellular gradients
of morphogenetic proteins. VEGF, an essential factor for capillary
formation, is stored in the extracellular matrix, but the mechanisms
by which it and other matrix-bound morphogens are mobilized to
form spatial gradients are poorly understood. Here, we suggest an
efficient mechanism for morphogen gradient generation by subtle
biophysical forces in an in vitro model of capillary morphogenesis.
Using a fibrin-bound VEGF variant that is released proteolytically
to mimic the in vivo situation, we report that low levels of
interstitial flow act synergistically with VEGF to drive endothelial
organization, whereas each stimulus alone has very little effect. To
help account for this synergy, we show how these slow flows can
bias the distribution of cell-secreted proteases, which leads, inter-
estingly, to the creation of an increasing VEGF gradient relative to
the cell and skewed in the direction of flow. In contrast, diffusion
alone can only account for symmetric, decreasing autocrine gra-
dients. Indeed, branching of capillary structures was biased in the
direction of flow only with the combination of VEGF and flow. This
work thus demonstrates a general mechanism of morphogen
gradient generation and amplification by small ubiquitous me-
chanical forces that are known to exist in vivo