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Departments of 1 Pediatrics and 2 Anesthesiology, University of Virginia, Charlottesville, Virginia 22908
Congenital heart
lesions resulting in increased pulmonary blood flow are common and if
unrepaired often lead to pulmonary hypertension and heart failure.
Therefore, we hypothesized that increased pulmonary blood flow without
changes in pressure would result in remodeling of the pulmonary
arterial wall. Furthermore, because the vasodilator nitric oxide is
produced by the lung, is regulated by flow in the systemic circulation,
and has been associated with the regulation of smooth muscle cell
proliferation, we hypothesized that increased pulmonary blood flow
would result in altered expression of endothelial nitric oxide synthase
(eNOS). To study this hypothesis, 42-day-old Sprague-Dawley
rats had creation of an aortocaval shunt to increase pulmonary blood
flow for 6 wk. The shunt resulted in a significant increase in the
heart- and lung-to-body weight ratios (>2-fold;
P < 0.05) without significant alteration of pulmonary or systemic blood pressures. Significant thickening of the pulmonary arterial medial wall developed, with increased muscularization of small (50-100 µm)- and medium
(101-200 µm)-sized arteries as evidenced by 
-actin smooth
muscle staining. Proliferating cell nuclear antigen staining and
bromodeoxyuridine labeling did not detect proliferating smooth muscle
cells in the vascular wall. eNOS Western and Northern blot analyses and
immunohistochemical staining demonstrated that eNOS protein and mRNA
levels were not altered in the shunt lungs compared with sham controls.
Therefore, increased pulmonary flow without increased pressure resulted
in pulmonary artery medial thickening, without ongoing proliferation. Unlike chronic hypoxia-induced vascular remodeling, the pulmonary vascular remodeling resulting from increased pulmonary blood flow is
not associated with changes in eNOS.
shunt; proliferating cell nuclear antigen; congenital heart disease; endothelial nitric oxide synthase
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