Biomedical Engineering Reference
In-Depth Information
Endothelial dysfunction can lead to impaired production of these factors [
35
]. Once
ECs are activated in a diseased state, they may start to express factors that can
increase SMC proliferation and vasoconstriction. In pulmonary hypertension, EC
dysfunction results in the reduction of pro-vasodilator and antiproliferative mole-
cules such as nitric oxide, while pro-vasoconstrictive and pro-proliferative mole-
cules such as ET-1 are increased.
Nitric oxide (NO) is an essential signaling molecule in many physiological
processes; it is responsible for resting pulmonary vasorelaxation and vascular tone.
Endothelial NO synthase (eNOS) catalyzes the conversion to produce NO; this
enzyme is expressed in ECs and SMCs and can react with a variety of molecules.
eNOS can be modified by biomechanical stimuli such as shear stress and increased
pulmonary blood flow [
46
]. eNOS is a constitutive enzyme controlled by the
intracellular calcium concentration, when shear stress increases the calcium
concentration an increased production of NO results in the inhibition of the
underlying SMCs. If there is a sudden decrease in NO, SMCs will contract due to
the withdrawal of the inhibitory effect of NO production [
47
]. Along with the
vasconstrictive effect, NO is also antiproliferative, thus a reduction in its pro-
duction could contribute to proliferation of SMCs. Decreased levels of eNOS have
been observed in patients with pulmonary hypertension [
48
].
Endothelin-1 (ET-1) is an amino acid polypeptide produced by vascular ECs,
and binds to SMC through the ET
A
receptor. ET-1 is a vasoconstrictive and pro-
proliferative molecule, which induces dysfunction of ECs, SMCs, and fibroblasts.
ET-1 levels are increased in patients with pulmonary hypertension. In hypertensive
animals, ET-1 was abundant in the ECs of pulmonary arteries with medial
thickening and intimal fibrosis and showed a strong correlation with increased
pulmonary vascular resistance. ET-1 receptors are highly expressed in the media
of arteries and on SMCs, where they mediate vasoconstriction and proliferation.
The level of ET-1 is inversely proportional to the magnitude of blood flow and
cardiac output.
Angiotensin-1 converting enzyme (ACE) is a circulating enzyme that con-
tributes to vasoconstriction and increased blood pressure; it is secreted by endo-
thelial cells. ACE converts angiotensin-I to angiotensin-II, a vasoconstrictor, and it
degrades bradykinin, a vasodilator. ACE is highly expressed in the lungs. Studies
have shown that Angiotensin-II induces pulmonary vasoconstrcition and ACE
inhibitor has prevented the development of pulmonary hypertension in animal
models [
49
].
Platelet derived growth factor (PDGF) regulates cell growth and division, and is
synthesized by many different cell types including SMCs and ECs. PDGF is a
heterodimer that consists of two chains, A and B, which are 40 % homologous to
each other. PDGF is an important mitogen for mediating SMC hyperplasia,
hypertrophy, migration, and for vascular remodeling. Over expression of this
growth factor can lead to a diseased state. High levels of PDGF have been found in
patients with pulmonary hypertension, indicating that this growth factor is critical
molecule
contributing
to
elevated
resistance
and
pressure
in
the
pulmonary
vessels.
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