CONCLUSIONS
Stretching and mechanical stress are the initial mechanisms that trigger
MV adaptation to a new hemodynamic situation. Increase in leaflets area
and length and in chordal length is due to collagen uncrimping, which is
able to increase leaflets and chordal dimensions by 30 to 50%. To
maintain the same thickness, it is necessary to produce more collagen by
activated VICs, either because of mechanical stress or TGF-β activation.
The purpose is to maintain the same thickness even with a longer or
larger MV, but the process can become dysregulated, such as in presence
of an AMI.
TGF-β is present in the MV in a latent form. Many stimuli (stretching,
mechanical stress, inflammation, turbulent flow, and others), can
trigger the release of active TGF-β, which binds to a membrane receptor
that in turn activate signal transducers that accumulate into the nuclei
and transcripts specific genes, targeted to induce fibrotic changes.
Targets can be quiescent VICs, present in the ECM, that change in
activated myofibroblasts, but VECs as well. As a consequence, VECs
activate and lose the adhesion to neighbor cells. The basement membrane
is eroded by enzymatic secretion and the VECs migrate into the ECM,
where transition to mesenchymal cells, which in turn can differentiate
in other cells, such as myofibroblasts, etc. Myofibroblasts produce
collagen and the excess of collagen production causes an excessive
accumulation of ECM components. If this process becomes dysregulated, as
often it happens after AMI, permanent scarring and increased leaflet
fibrosis occurs. After a MI, VECs undergo EndMT, VICs are activated to
become myofibroblasts that secrete and compact ECM, and there is
evidence for valve neovascularization and leukocyte
infiltration6,26,36. Infiltrating macrophages and
leukocytes release growth factors and cytokines, such as TGF-β family
members, which can further promote angiogenesis, collagen production,
attraction of additional inflammatory cells, and transform VICs to
myofibroblasts that also secrete growth factors and cytokines.
Activated TGF-β can induce phenotype changes in quiescent VICs, which
change morphology and function, contributing to pathologic changes. In
the ischemic setting, excessive TGF-β signaling occurs, that stimulates
exuberant EndMT, resulting in profibrotic changes of the leaflets, such
as markedly increased thickness, cellular proliferation, and excessive
ECM turnover with collagen deposition.
It is not clear if the activation of the ECs is directly dependent by
the trigger, such as mechanical stress, or induced by TGF-β since the
beginning.