Overexpression of endothelin-1 and enhanced growth of pulmonary
artery smooth muscle cells from fawn-hooded rats.
Zamora, Martin R., Thomas J. Stelzner, Sally Webb, Ralph J. Panos,
Laura J. Ruff, and Edward C. Dempsey.
Cardiovascular Pulmonary (CVP) Research Laboratory, Division of
Pulmonary Sciences, Univ. of Colorado Health Sciences Center, and
Denver Veterans Administration Medical Center, Denver, Colorado
80262; Department of Pediatrics, Univ. of South Carolina, Charleston,
South Carolina, and Division of Pulmonary Medicine, Northwestern
University Medical School, Chicago, Illinois 60611
APStracts 2:0147L, 1995.
Increased production of endothelin-1(ET-1) has been detected in lungs
of Fawn-hooded rats (FHR) with idiopathic pulmonary hypertension.
Accelerated pulmonary artery (PA) smooth muscle cell (SMC)
proliferation contributes to vascular remodeling in these rats. We
hypothesized that PA SMC would be an important site of enhanced ET-1
expression in FHR lung, that these SMC would have increased growth
compared to cells from a normotensive strain, and that this locally
produced ET-1 would contribute to the increased growth of these
cells. We found that isolated FHR PA SMC overexpressed preproET-1
mRNA and produced more ET-1 peptide compared to cells from
normotensive Sprague-Dawley control rats (SDR). PA SMC from FHR had
increased growth compared to control cells under conditions of serum
withdrawal (0.1%), submaximal serum stimulation (0.3%; a condition
previously found to be required for detection of growth in response
to the co-mitogen, ET-1), and maximal serum stimulation (10%).
Enhanced growth of FHR PA SMC in the presence of 0.3% serum, but not
under the other test conditions, was inhibited by the ETA receptor
antagonist, BQ123. In summary, PA SMC from rats with idiopathic
pulmonary hypertension overproduce ET-1. This overproduction
contributes to the enhanced growth of FHR PA SMC in the presence of
0.3% serum. These cells also possess other unique growth
characteristics that are independent of ET-1. Together, these ET-1
dependent and independent growth properties likely contribute to the
hyperplasia of FHR PA SMC found in vivo.
Received 1 June 1995; accepted in final form 11 August 1995.
APS Manuscript Number L176-5.
Article publication pending Am. J. Physiol. (Lung Cell. Mol.
Physiology).
ISSN 1080-4757 Copyright 1995 The American Physiological Society.
Published in APStracts on 24 August 1995.