Regulation of endothelin-1 gene expression by cell shape and the microfilament network in vascular endothelium.
Endothelial synthesis and release of endothelin-1 (ET-1) are exquisitely regulated by external shear and strain. We tested the hypothesis that manipulation of endothelial cell shape can regulate ET-1 gene expression. Treatment of bovine aortic endothelial cell (BAEC) monolayers with cytochalasin D disrupted F-actin and induced cell retraction and rounding, in parallel with time- and dose-dependent specific decreases in ET-1 mRNA levels. Treatments with forskolin, phorbol 12-myristate 13-acetate, staurosporine, and genistein also induced cell shape change and decreased F-actin staining and ET-1 mRNA levels. BAEC plated onto nonadhesive petri dishes coated with decreasing concentrations of synthetic RGD polymer showed RGD dose-dependent decreases in cell spreading and in F-actin microfilament elaboration. These changes were specifically accompanied by decreases in ET-1 peptide secretion (60%) and, via posttranscriptional mechanisms, ET-1 mRNA (94%) and were not due to decreased cell-cell contact. We conclude that the shape and microfilament network of endothelial cells are potent posttranscriptional regulators of ET-1 gene expression.
Malek
A M
AM
Department of Neurosurgery, Brigham and Women's Hospital, Boston, Massachusetts, USA.
Lee
I W
IW
Alper
S L
SL
Izumo
S
S
D008841:Actin Cytoskeleton / Q000502:physiology* / Q000648:ultrastructure*; D000199:Actins / Q000187:drug effects; D000818:Animals; D001011:Aorta; D002417:Cattle; D048429:Cell Size; D002478:Cells, Cultured; D005576:Colforsin / Q000494:pharmacology; D015638:Cytochalasin D / Q000494:pharmacology; D003599:Cytoskeleton / Q000187:drug effects / Q000502:physiology; D019332:Endothelin-1 / Q000096:biosynthesis*; D004730:Endothelium, Vascular / Q000166:cytology* / Q000502:physiology*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D019833:Genistein / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis; D019311:Staurosporine / Q000494:pharmacology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects
D000199:Actins; D019332:Endothelin-1; D012333:RNA, Messenger; D005576:Colforsin; D015638:Cytochalasin D; D019833:Genistein; D019311:Staurosporine; D013755:Tetradecanoylphorbol Acetate