Vascular Cell Physiology Under Shear Flow: Role of Cell Mechanics and Mechanotransduction - Mechanical and Chemical Signaling in Angiogenesis - page 134

Transforming growth factor beta (TGF-b) is a protein that controls prolifera-
tion, and cellular differentiation. TGF-b is a modulator of smooth muscle mor-
phology, phenotype, and stimulates extracellular matrix production, it is secreted
in latent form by ECs. TGF-b induces the production of collagen and other
extracellular matrix proteins, such as fibronectin, and has been shown to remodel
tissues. The different isoforms of this growth factor are encoded by distinct genes
and have specific functions for tissue and development. Transforming growth
factor beta 1 (TGF-b1) mRNA is expressed in ECs. TGF-b1 exerts its effects on
SMCs including, inhibiting proliferation, altering extracellular matrix synthesis
and cell differentiation. However, in the pulmonary artery SMCs from patients
with pulmonary hypertension, TGF-b1 caused enhanced cell proliferation com-
pared to an inhibitory effect in normal cells [ 50 , 51 ].
7 Mechanotransduction
ECs respond to flow through mechanotransducers, which convert the mechanical
signal of fluid shear stress to biochemical signals. Many mechanotranducers have
been identified, including ion channels, integrins, adhesion proteins, glycocalyx,
primary cilia, tyrosine kinase receptors, G-protein coupled receptors, and cyto-
skeleton. However, the interplay and coordination between these mechanotrans-
ducers remains ill-defined.
Initial responses to fluid shear stress include the activation of mechanosensitive
ion channels and oscillations in intracellular calcium [ 52 ]. These changes occur in
a matter of seconds. Several minutes of fluid shear stress induces changes in
signaling cascades including mitogen-activated kinases (MAPK) and activation of
transcription factors including nuclear factor kappa B (NFjB) [ 52 ]. It has been
suggested that cells can distinguish between athero-protective and athero-prone
fluid shear stress through mechanosensory proteins at the cell surface that transmit
the signal throughout the cell via the cytoskeleton to nucleus, focal adhesions, and
cell-cell contacts [ 53 , 54 ]. This cytoskeleton-mediated distribution of signaling
throughout the cell is known as ''decentralization theory'' [ 54 ].
Evidence suggests that many parts of a cell respond to the mechanical stimu-
lation imposed by fluid shear stress including the cell surface, cell-cell junctions,
focal adhesions, and the nucleus [ 53 - 55 ]. These cellular locations are connected
by the cytoskeleton [ 53 ]. The cytoskeleton is critical in the transmission of the
apical shear stress signal to the basal integrins or lateral adhesion proteins, which
is where mechanotransduction events occur. The decentralization model suggests
that mechanotransduction is transmitted by the cytoskeleton throughout the cell,
thus initiating the myriad of fluid shear stress-induced cell responses. An active
area of research in the past decade has aimed to better understand the complicated
orchestration by small Rho GTPases on such responses, such as the potentially
separate, but intimately linked, microtubule regulation of cell polarity [ 56 , 57 ] and