Page 113 - Advances in Biomechanics and Tissue Regeneration

6.4 MECHANOSENSING AND MECHANOTRANSDUCTION 109

the organ level (vessel mechanoadaptation), the tissue level (ECM prestressing and synthesis/degradation), the cel-
lular level (traction forces applied onto the ECM, see Section 6.3.2.1), the subcellular level (FAs and actin/myosin bun-
2+
dles), and even the molecular level ([Ca ] i ). These findings suggest that the cell is able to adapt its proper stress state
2+
through the regulation of [Ca ] i , the cytoskeleton and FA turnover, and by controlling its surrounding ECM as well.
Experimental studies of Matsumo et al. [123] showed a change of the intramural strain distribution in response to SMC
contraction (and relaxation) on radially cut aortic rings and confirmed that SMCs actively adapt their contractile state
to keep the intramural stress uniform. In summary, SMCs can both work actively (through contraction/relaxation) and
passively by deposition and organization of the ECM [21].
That is why SMCs may undergo a phenotypic switching toward a synthetic one under several stimuli (see
Section 6.4.2). Through phenotypic switching, SMCs tend to remodel their ECM to go back to a preferred state and
face the variations of their environment. Humphrey has well described this equilibrium state saying: “When a homeo-
static condition of the blood vessel is disturbed, the rate of tissue growth is proportional to the increased stress” [27].
But SMCs lose their contractility in return and may irrevocably affect the wall vasoactivity in which they may have a
key role [21, 23, 50]. In fact, Humphrey suggests in his review that fully contractile SMCs can react mainly to circum-
ferential wall stress (150 kPa in physiological conditions) with 100 kPa equivalent traction forces exerted on their
ECMs while synthetic SMCs may only apply 5 10 kPa [21].

6.4.5 Consequences for Aortic Tissue
Reduction or loss of SMC contractility alters the stress distribution across the aortic wall [41, 52, 56, 97]. In reaction,
the development of synthesis abilities ensures recovery processes by ECM remodeling. SMCs keep a key role in the
aortic wall remodeling. In ATAAs, they tend to adapt their response through complex signaling pathways. An impor-
tant one is Rho kinase (ROCK), which is mainly involved in cytoskeleton turnover for the control of cell shape and
movement during migration [23]. The Rho kinase seems to influence the formation of α-SMA thin filaments and
the regulation of FAs that are involved in SMC contractility and anchoring to the ECM [24, 44, 96, 133]. Moreover,
the oxidative stress induced by ATAAs enhances the inflammatory response of SMCs, increasing MMP synthesis
and the further disruption of elastin fibers [18].
Remodeling was shown to be uneven in human [13] and porcine [12] aortic tissues. The authors highlighted that the
outer curvature of the ATAAs is more affected. Remodeling implies phenotypic switching toward a synthetic pheno-
type able to synthesize both ECM compounds (i.e., collagen and glycoproteins) and MMPs to degrade the
“dysfunctional” ECM, leading to ECM wear [27, 29, 40, 56]. Likewise, elastin degradation results in a permanent
decrease of the elastin/collagen ratio because elastic fibers cannot be regenerated in adulthood [9]. On top of the
induced stiffening, the ability of SMCs to restore a healthy state is altered as well, as it was shown that elastin is also
important for activating actin polymerization [37]. Moreover, SMCs undergo a general apoptosis to reduce their num-
ber when they sense an inappropriate chemomechanical state, inducing further reduction of elasticity and mechanical
resistance through a vicious circle loop [18, 28, 42, 132].

6.4.6 Toward an Adaptation of SMCs in ATAAs?

Any disruption of the mechanical or chemical homeostasis is interpreted by the SMCs as a distress signal, and sev-
eral recovery processes can be activated in reaction, but the regulation loop is similar to a vicious circle because of the
complexity to return naturally to equilibrium (Fig. 6.10). Interestingly, in hypertension, the increase of wall stress
results in an increase in the arterial diameter [27, 131]. Conversely, a decrease in mean wall stress leads to atrophy
[27]. Because the (S) SMCs can recover their (C) phenotype once the tissue returns to its original homeostatic stress,
the phenotypic switching seems to be a reversible process [32, 41, 56]. These observations suggest a two-way mechan-
oadaptive process. But once affected by ATAAs, remodeled aortic ECM is known not to reach complete recovery, par-
ticularly because disrupted elastic fibers cannot be rebuilt in adulthood [9]. Aortic tissue would, therefore, evolve more
or less quickly according to some factors that may slow it down. As the review study of Michel et al. [15] has already
pointed out, ATAAs may result in some epigenetic modifications that have an influence on the cellular response. It
could be defined as the acquisition of new constant and heritable traits without requiring any change in the DNA
sequence, which results, for instance, in gene modulation. The suggested theory explains that SMC reprogramming
is likely to induce a progressive dilatation of the aorta without dissection, whereas no SMC reprogramming promotes
acute rupture of the wall [15]. Finally, it is well accepted that SMCs play a major role in controlling the wall evolution
after aortic injury, either toward partial recovery of initial mechanical properties or fatal rupture through dissection.

I. BIOMECHANICS