Endothelin 1: mitogenic activity on pulmonary artery smooth muscle cells and release from hypoxic endothelial cells.
Endothelin, a recently described vasoconstrictor, has been shown to be a mitogen for vascular smooth muscle cells from systemic arteries and might play a role in pulmonary vascular remodeling produced by chronic exposure to hypoxia. We examined the effects of endothelin on proliferation of pulmonary artery smooth muscle cells and the effects of hypoxia and normoxia on the synthesis and secretion of endothelin by endothelial cells. Our results indicate that endothelin significantly increased the incorporation of [3H]thymidine by porcine pulmonary artery smooth muscle cells (122 +/- 4% to 168 +/- 13% of controls, with concentrations of endothelin from 1 to 1000 ng/ml). When tested on bovine pulmonary artery smooth muscle cells, endothelin increased [3H]thymidine incorporation over controls by approximately 140%; cell counts were increased by 107 +/- 4% and 122 +/- 7% at doses of 100 ng/ml and 1000 ng/ml, respectively. The secretion of endothelin by porcine endothelial cells was not affected by hypoxia (3520 +/- 138 pg/ml/10(6) cells in hypoxia vs 3770 +/- 326 pg/ml/10(6) cells in normoxia). Transforming growth factor-beta 1 stimulated the release by normoxic, and to a lesser degree by hypoxic, porcine endothelial cells of endothelin (4716 +/- 43 pg/ml/10(6) cells vs 4074 +/- 106 pg/ml/10(6) cells). Taken together, our results indicate that endothelin is weakly mitogenic for pulmonary artery smooth muscle cells, but may not significantly contribute to the remodeling seen in hypoxic pulmonary hypertension.
Hassoun
P M
PM
Department of Medicine, New England Medical Center Hospitals, Boston, Massachusetts 02111.
Thappa
V
V
Landman
M J
MJ
Fanburg
B L
BL
D000818:Animals; D002417:Cattle; D002455:Cell Division / Q000187:drug effects; D015687:Cell Hypoxia / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D016232:Endothelins / Q000096:biosynthesis* / Q000494:pharmacology*; D004727:Endothelium / Q000378:metabolism; D000860:Hypoxia; D066298:In Vitro Techniques; D009131:Muscle, Smooth, Vascular / Q000166:cytology*; D011651:Pulmonary Artery / Q000378:metabolism*; D011863:Radioimmunoassay; D013552:Swine; D016212:Transforming Growth Factor beta
D016232:Endothelins; D016212:Transforming Growth Factor beta