Mechanosensory Pathways in Angiocrine Mediated Tissue Regeneration - Mechanical and Chemical Signaling in Angiogenesis - page 23

Fig. 1 Early molecular response of endothelial cells to shear stress. Endothelial phenotype is
constantly modulated by both biomechanical and biochemical stimuli. Biochemical stimuli
include hormones, growth factors, cytokines, etc. that are delivered to the cell via autocrine or
paracrine mechanisms. Hemodynamic forces result in hydrostatic pressure, cyclic strain, and
shear stress. Different mechanosensors play specialized roles in interpreting this stress in
endothelial cells. These sensors include ion channels (TRP, P2X4, K + ,Cl - channels) [ 26 ],
integrins, platelet endothelial cell adhesion molecule-1 (PECAM-1), VE-cadherin, caveolae, G
proteins, glycocalyx, and the endothelial cytoskeleton [ 27 ]. The activity of ion channels leads to
an influx in Ca 2+ , which results in vasodilator production (namely nitric oxide), prostacyclin, and
Endothelium-Derived Hyperpolarizing Factor (EDHF). Shear stress travels through the
cytoskeleton to the endothelial surface, where either integrins or PECAM-1 and VE-cadherin
are activated sequentially. Activated integrins bind to adaptor protein Shc as well as numerous
kinases, including focal adhesion kinase (FAK). Shear stress also triggers tyrosine phosphor-
ylation of PECAM-1 and localization of SHP-2 and Gab1 near the cell junction. This will
subsequently results in ERK phosphorylation. Shear activation of (VEGF)-A receptor-2
(VEGFR2) at the luminal surface leads to the recruitment of phosphatidylinositol 3 kinase
(PI3 K), which itself leads to the activation of Akt and eNOS. The activation of ERK and the
phosphorylation of serine 1179 of eNOS at caveolae by shear have also been documented. Shear
stress is rapidly followed by G protein activation and results in the activation of Ras and
extracellular signal-regulated kinases-1/2 (ERK1/2). Deformation of the luminal surface will
result in direct shear stress-induced signaling through the glycocalyx (via NO production)
(adapted from [ 28 , 29 ])
force sensation, namely ion channels, cell-matrix and cell-cell junction molecules,
Tyrosine Kinase Receptors [(VEGF)-A receptor-2 (VEGFR2)], caveolae,
G-protein coupled receptors/G-proteins, glycocalyx, and the endothelial cyto-
skeleton (reviewed in [ 20 , 27 ]). Mechanotransduction of hemodynamic forces
plays a central role in regulation of arterial diameter. This process is orchestrated