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Biomechanical Determinants of Endothelial Sprouting and Morphogenesis
Author(s) -
Song Jonathan W,
Munn Lance L.
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.683.10
Subject(s) - morphogenesis , filopodia , microbiology and biotechnology , rhoa , angiogenesis , sprouting angiogenesis , chemistry , morphogen , shear stress , biology , biophysics , anatomy , materials science , actin , neovascularization , signal transduction , cancer research , biochemistry , composite material , gene
Angiogenesis requires the coordinated growth and migration of endothelial cells (ECs), and each EC residing in a vessel wall integrates local signals to determine whether it remains quiescent or undergoes morphogenesis. Among these signals include vascular endothelial growth factor (VEGF), a well characterized morphogen which induces the formation of specialized “tip cells” that guide sprouts, and mechanical forces due to blood flow such as shear stress tangential to the endothelial surface and interstitial plasma flow across the vessel wall. Using a microfluidic tissue analogue of angiogenic sprouting, we found that physiological fluid shear stress (3 dyn/cm 2 ) inhibits EC morphogenesis (sprouting and invasion into the 3‐D matrix) in a nitric oxide‐dependent manner and interstitial flow (2.5–35 μm/s) increases the rate of morphogenesis. Surprisingly, invading ECs not only detected the direction of VEGF gradients but also showed dramatic differences in morphogenesis depending on the direction of interstitial flow. Endothelial tip cells producing filopodia preferentially protruded against the direction of interstitial flow and in the direction of an increasing VEGF gradient. However, dominant‐negative RhoA ECs maintain the ability to respond to VEGF gradients by producing filopodia but no longer respond to interstitial flow. These results suggest that ECs integrate signals from fluid forces and local VEGF gradients to mediate endothelial sprouting and that RhoA is involved in flow‐induced tip cell morphogenesis. Research support: NIH T32CA073479 and NIH R01CA149285.