Smooth Myocytes - Tissue Functioning and Remodeling in the Circulatory and Ventilatory Systems - page 407

that become unnecessary. Inhibition of cell cycle-controlling ubiquitin ligases or
proteasome represses vSMC proliferation and prevents change to the synthetic
phenotype [ 749 ].
When the endocytic phenotype is achieved, cationic proteins are mainly
endocytosed by an absorptive mechanism, involving interactions with the negative
charges of the glycocalyx; anionic proteins such as LDLs interact mainly with
LDLR receptors and modified LDLs with scavenger receptors.
In atherosclerosis characterized by an osteoblastic phenotype, foci of calcifica-
tion are likely linked to cell death and membrane-annexin-rich particle release,
which supports calcium-phosphate concentration; extracellular free DNA triggers
precipitation.

8.5.3.1 Mechanical Signals in Phenotype Change

Regulation of cell functions, such as proliferation and differentiation, relies not only
on chemical compounds such as growth factors, but also on physical and mechanical
signals, in particular geometrical and rheological features of the extracellular matrix
and eventual anisotropy that influence cell spreading and curvature. 34
Deformations of the plasma membrane activates mechanosensitive immersed
proteins, such as mechanically gated ion channels, receptors, and cell adhesion
molecules. In particular, integrins that cluster to build focal adhesions tether the
intracellular actin cytoskeleton to the extracellular matrix. Focal adhesions are
signalling hubs that contain kinases, such as FAK, MAPKs, and Src, and small
GTPases such as Ras. The actin cytoskeleton also connects to the nucleus and its
nucleoskeleton with intermediate filaments and lamins, via nestins (Vol. 1 - Chap. 4.
Cell Structure and Function). Nuclear strains and stresses exerted on nuclear
lamins and other nucleoskeletal constituents and changes in interactions of nuclear
structural proteins with chromatin may modulate the chromatin organization and
interplays with DNA-binding proteins, thus controlling gene expression patterns.
Furthermore, mechanical stresses are converted into chemical signals that can be
transmitted down to to the nucleus to modify gene expression.
In particular, effectors of the Hippo pathway, or kinase (STK3 and STK4)
cassette, Yes-associated protein (YAP) and transcriptional coactivator with PDZ-
binding motif (TAZ; or WWTR1) relay mechanical cues to the nucleus [ 750 ].

and impedes its phosphorylation (that can target substrates for ubiquitination) due to enhanced
phosphatase activity. Nitric oxide inhibits proteasome via thiol nitrosylation as well as UbCh10
ubiquitin conjugase [ 749 ].
34 Myogenic stem and precursor cells cultured on substrates mimicking muscle rheological proper-
ties have a greater capacity to self-renew than those cultured on stiffer or softer matrices [ 750 ]. In
addition, contractility of cultured vascular smooth myocyte depends on substrate rigidity.