Effects of bone morphogenic proteins and transforming growth factor-beta on In-vitro production of endothelin-1 by human pulmonary microvascular endothelial cells.
BACKGROUND
Altered endothelial cell (EC)-derived mediator levels, including increased endothelin-1 (ET-1), are hallmarks of human pulmonary arterial hypertension (PAH). Gene mutations for receptors for bone morphogenic proteins (BMP), or transforming growth factor-beta (TGF-beta) cause heritable PAH. The effects of BMPs and TGF-beta on ET-1 production by human pulmonary microvascular EC (HMVEC-LBl) are unknown.


METHODS
HMVEC-LBl were exposed in-vitro to BMPs 2, 4, and 7 or TGF-beta1 in basal or complete medium. ET production was measured, as well as total cellular protein. Levels of Smad 5 and phosphorylated Smads 1/5 were also measured.


RESULTS
BMP-4 did not increase ET-1 while BMP-2 increased it minimally in basal medium. BMP-7 increased ET-1, but only at 100 ng/ml. By contrast, TGF-beta increased ET-1 throughout most of the studied dose range. All BMPs and TGF-beta increased levels of phosphorylated Smads 1/5 without depleting levels of Smad 5.


CONCLUSIONS
With the exception of BMP-7 at high-concentrations, the BMPs that interact with BMP receptor 2, the receptor implicated in heritable PAH, do not or minimally modulate in-vitro constitutive ET-1 production by HMVEC-LBl. TGF-beta increases ET-1 synthesis, and this may have clinical relevance in PAH.
Star
Gregory P
GP
Center for Pulmonary Vascular Disease, Division of Cardiology and Lady Davis Institute for Medical Research, Sir Mortimer B. Davis Jewish General Hospital, McGill University, Montreal, Quebec, Canada.
Giovinazzo
Michele
M
Langleben
David
D
D055396:Bone Morphogenetic Protein 2 / Q000378:metabolism / Q000494:pharmacology; D055415:Bone Morphogenetic Protein 4 / Q000378:metabolism / Q000494:pharmacology; D055419:Bone Morphogenetic Protein 7 / Q000378:metabolism / Q000494:pharmacology; D002478:Cells, Cultured; D019332:Endothelin-1 / Q000096:biosynthesis*; D004730:Endothelium, Vascular / Q000378:metabolism*; D006801:Humans; D008168:Lung / Q000098:blood supply / Q000166:cytology / Q000378:metabolism; D008833:Microcirculation; D010766:Phosphorylation / Q000187:drug effects; D051898:Smad1 Protein / Q000378:metabolism; D051902:Smad5 Protein / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism / Q000494:pharmacology
D055396:Bone Morphogenetic Protein 2; D055415:Bone Morphogenetic Protein 4; D055419:Bone Morphogenetic Protein 7; D019332:Endothelin-1; C497399:SMAD1 protein, human; C497797:SMAD5 protein, human; D051898:Smad1 Protein; D051902:Smad5 Protein; D053773:Transforming Growth Factor beta1