Tissue Development, Repair, and Remodeling - Tissue Functioning and Remodeling in the Circulatory and Ventilatory Systems - page 737

Cardiac hypertrophy is induced by sustained pressure overload. Multiple hyper-
trophy signaling pathways are triggered by pressure: PP3-NFAT and PI3K-PKB
axes and ERK1 and ERK2 kinases. The calcium-dependent PP3 phosphatase
influences the growth and gene expression of the myocardium. Calcineurin (PP3)
binds to calsarcins . 76 Calsarcin-1 impedes the functions of PP3 [ 1483 ]. The absence
of calsarcin-1 enhances the cardiac growth response to pressure overload and favors
hypertrophy.
Vasoactive substances such as angiotensin-2 are secreted by the overloaded
myocardium. Angiotensin-2 induces superoxide anion production in cardiomy-
ocytes and heart hypertrophy. Cardiac hypertrophy is mediated by myocardial
oxidative stress, Rac1 GTPase, and NADPH oxidase [ 1484 ].
Cardiac hypertrophy caused by chronic hypertension is associated with fibrosis,
such as in myocardial infarction. Fibrosis due to hypertension involves reciprocal
interactions between stimulatory and inhibitory factors, resulting in increased depo-
sition of collagen-1 and -3 within the adventitia of coronary arteries (perivascular
fibrosis), which extends progressively.

11.8.2 Vessel Wall Remodeling

Blood vessels are subjected to mechanical forces that are implicated in vascular
development, adaptation, and genesis of vascular diseases. Vessel caliber changes
depend on a combination of wall wetted surface and intramural stresses. Blood
pressure changes quickly induce tissue remodeling. Hypoperfusion reduces lumen
caliber and media mass, whereas hyperperfusion increases these two quantities.
Chronic increases in arterial blood flow lead to vessel enlargement and reduction
of mechanical stress to physiological values.
Arteries enlarge in response to increased blood flow and wall shear stresses.
Gaps in the internal elastic lamina have been observed in arteries exposed to
high blood flow, whereas EC proliferation assures a continuous lining [ 1485 ].
Artery enlargement and adaptive remodeling is associated with FGF2 expression
which acts on endothelial and smooth muscle cells [ 1486 ]. Conversely, upregulation
of endothelin-1 and downregulation of nitric oxide can initiate and mediate the
remodeling after blood flow reduction.
Step pressures induce a bore increase followed by a reactive SMC contrac-
tion (quick adaptation). Delayed slow structural changes are characterized by
SMC proliferation. The time required by internal vessel radius variations after
flow rate changes in large arteries is few days to weeks [ 1487 ]. Wall remod-
eling is characterized by a rapid first stage of geometrical changes. Besides,
hypertension attenuates endothelial-to-endothelial or smooth muscle-to-endothelial

76 The calsarcin family contains proteins of the sarcomeric Z disc (Sect. 5.3.4 ).