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Departments of 1 Pathology and 2 Medicine, Center for Lung Research, Vanderbilt University Medical Center, Nashville, Tennessee 37232-2650
Endothelin-1 (ET-1) is a potent vasoconstrictor that
causes sustained constriction of the pulmonary artery and modulates
normal vascular tone. Endothelial cells were thought to be the major source of ET-1, but recent studies show that vascular smooth muscle cells (SMCs) are also capable of its synthesis. We examined the ET-1
and endothelin-converting enzyme-1 (ECE-1) system in cells cultured
from two adjacent layers, subendothelial (L1) and inner medial (L2), of
normal sheep main pulmonary artery and the response of this system to
exogenous ET-1 and transforming growth factor-
1 (TGF-1). End
points include assessment of preproET-1 (ppET-1) and ECE-1 gene
coexpression, measurement of intracellular and released ET-1, and ECE-1
activity. RT-PCR analysis revealed that ppET-1 and ECE-1 transcripts
were greater in L1 than in L2 cells. The L1 cells also synthesized (L1,
3.2 ± 0.1; L2, 1.2 ± 0.1 fmol/106 cells) and released
(L1, 9.2 ± 0.5; L2, 2.3 ±0.1 fmol/ml) greater amounts of ET-1 than
L2 cells. The L2 cells internalized exogenous ET-1 in a dose-dependent
manner (EC50 8 nmol/l) and were more responsive to
exogenous ET-1 than L1 cells, showing upregulation of both the ppET-1
and ECE genes. TGF-1 downregulated ET-1-stimulated ppET-1 and ECE-1
transcripts but only in L2 cells. In addition, L1 cells showed greater
ECE-1 activity than L2 cells, and in both, the activity was sensitive
to the metalloprotease inhibitor phosphoramidon. We conclude that the
ET-1 system in L1 and L2 cells is distinct. The data suggest that the
two cell types have diverse functions in the arterial wall; the L1
cells, like endothelial cells, provide a local source of ET-1; and
since the L2 cells are more responsive to exogenous ET-1, they are
likely to affect normal pulmonary vascular tone.
endothelin-converting enzyme; reverse transcriptase-polymerase chain reaction; smooth muscle cells; cell heterogeneity; endothelin-1; smooth muscle cell
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