Mechanosensory Pathways in Angiocrine Mediated Tissue Regeneration - Mechanical and Chemical Signaling in Angiogenesis - page 24

by the production and release of autacoids by the endothelial cells affected. Nitric
oxide (NO), prostacyclin (PGI2), and endothelin-1 (ET-1) are the best-character-
ized endothelium-derived autacoids, the first two being vasodilators, and the last
being a vasoconstrictor. Two other factors have been suggested to play a signifi-
cant role in vasodilation: endothelium-derived hyperpolarizing factor (EDHF) and
reactive oxygen species (ROS) [ 27 , 34 ].
3.2 Integrin-Mediated Mechanotransduction
Integrins, as the main receptors that mediate the connection of the cytoskeleton to
the ECM, have been implicated in sensing mechanical forces [ 35 ]. When the
apical surface of an endothelial cell experiences shear stress due to blood flow, the
tension experienced by the cell is transferred to transmembrane integrins, which
undergo conformational changes and alter the phenotype of the cell. In order to
maximize adhesion, the cell needs to increase its surface area in contact with the
ECM so it flattens in a manner consistent with the blood flow. Tension at the
upstream end of the cell with then be greater than the tension at the downstream
end [ 35 ]. In integrin-mediated cell binding to the ECM, proteins in the ECM bind
to integrins attached to the cell's cytoskeleton. This linkage bears much of the
mechanical force inflicted on the cells, and as such may serve as a candidate
mechanotransducer.
Glycoproteins within the extracellular matrix can be displaced by both cyclic
stretching and shear stress. These interact with integrins that transmit the
mechanical signal intracellularly. Shear stress can cause endothelial cell integrins
to form clusters [ 36 ], associate with adaptor proteins such as Shc [ 37 ], and bind to
WOW-1, an antibody that specifically binds to a particular activated intergrin [ 38 ].
The cytoplasmic domains of integrins are often linked to intracellular proteins that
constitute the cytoskeleton as well as kinases, including focal adhesion kinase
(FAK), a key regulator of biochemical cascades triggered by mechanical forces.
Therefore, integrins serve as a signal transmitter between the cell and the ECM [ 27 ].
Vascular endothelial growth factor (VEGF) is a homodimeric glycoprotein and
a sub-family of the cysteine-knot growth factor superfamily, a platelet-derived
growth factor family [ 39 , 40 ]. They have profound involvement in signaling for
both vasculogenesis (the de novo formation of blood vessels) and angiogene-
sis (the growth of blood vessels from pre-existing vasculature). VEGF promotes
vasculogenesis during embryonic development, angiogenesis after injury and
within muscles following exercise, as well as new vessels that serve to bypass
older, blocked vessels.
Overexpression of VEGF can contribute to disease. Solid tumors require suf-
ficient blood supply after they reach a certain size. Tumor cells that have the
ability to express VEGF can therefore further expand and metastasize. VEGF over-
expression may also cause vascular diseases of the retina. Anti-VEGF therapies are
used to control or slow down the progression of diseases facilitated by VEGF