Biomedical Engineering Reference
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marked increase in vascular resistance and onset of right ventricular hypertrophy
leading to right-sided heart failure and death. Central to the pathogenesis of pulmo-
nary hypertension may be endothelial cell dysfunction, leading to imbalances in
vasodilator (decreased prostacyclin and NO) versus vasoconstrictors (increased
endothelin). Current approaches for treating pulmonary hypertension include sup-
plemental oxygen, anticoagulants and vasodilator drugs (calcium channel blockers,
prostacyclin), and inhaled NO.
Immunohistochemistry studies have localized NOS in pulmonary nerves, airway
epithelium and in pulmonary vascular cells, suggesting a role for NO in pulmonary
homeostasis. Endothelial NO-dependent relaxation of pulmonary arteries has been
reported to be impaired in other forms of pulmonary hypertension. The impaired
NO-dependent relaxation may result from several causes, including:
•
Direct damage and/or loss of endothelium
•
Reduced NO production secondary to impaired arginine uptake or decreased NO
synthase activity
Accelerated inactivation NOS mRNA, NOS, or NO
•
•
Reduced cGMP production secondary to impaired guanylate cyclase activity
In an ovine model of persistent pulmonary hypertension of the newborn,
endothelin-1 (ET-1) expression is increased, while eNOS expression is decreased.
In a study on pulmonary arterial endothelial cells isolated from fetal lambs, ET-1
secretion is increased by overexpression of Prepro-ET-1, a precursor of ET-1 (Sud
and Black
2009
). This results in activation of PKCd, which phosphorylates STAT3,
increasing its binding to the eNOS promoter. This in turn decreases eNOS promoter
activity, protein levels, and NO production. Thus, ET-1 can reduce eNOS expres-
sion and NO generation in fetal pulmonary artery endothelial cells through PKCd-
mediated activation of STAT3.
NO and Systemic Hypertension
Hypertension, a major cardiovascular risk factor and cause of mortality worldwide,
is thought to arise from primary renal abnormalities. However, the cause of most
cases of hypertension is unknown. Vascular tone, an important determinant of
blood pressure, is regulated by NO, which causes vascular relaxation by increasing
intracellular cGMP and activating cGMP-dependent protein kinase I (PKGI).
A study has shown that mice with a selective mutation in the N-terminal protein
interaction domain of PKGIa display inherited vascular smooth muscle cell abnor-
malities of contraction, abnormal relaxation of large and resistance blood vessels,
and increased systemic blood pressure (Michael et al.
2008
). Renal function studies
and responses to changes in dietary sodium in the PKGIa mutant mice are normal.
These data reveal that PKGIa is required for normal VSMC physiology and sup-
port the idea that high blood pressure can arise from a primary abnormality of
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