title: Expression of a recombinant preproendothelin-1 gene in arteries stimulates vascular contractility.
abstract: Endothelin (ET)-1 is a potent vasoconstrictor peptide that is elevated in cardiovascular diseases. However, the biological function of ET-1 gene expression within arteries in vivo has not been determined. The effects of ET-1 gene expression were investigated using gene-transfer methods on porcine vascular cells in vitro and porcine arteries in vivo. Transfection of vascular cells with a vector encoding for human preproendothelin-1 cDNA (pVR-ppET) resulted in significant increase in active ET-1 levels in culture supernatant compared with nontransfected cells (P < 0.05). This supernatant contracted rat aortic strips at concentrations 10-fold lower than synthetic ET-1 protein, which was inhibited by the ET-A receptor antagonist BQ-123. Transfection of pVR-ppET into pig iliofemoral arteries resulted in an increase in contractile responses to angiotensin I compared with control vessels (P < 0.05), in contrast to serotonin, phenylephrine, synthetic ET-1, and angiotensin II. A mitogenic effect of recombinant ET-1 on intimal cell growth was not observed. These findings demonstrate that expression of a recombinant ET-1 gene in vivo augments vascular contractility due to an increased sensitivity to angiotensin I, suggesting a role for ET-1 in the pathogenesis of cardiovascular diseases.
authors.affiliation: Department of Internal Medicine, University of Michigan, Ann Arbor 48109, USA.
authors.forename: E
authors.initials: E
authors.lastname: Schott
authors.forename: R C
authors.initials: RC
authors.lastname: Tostes
authors.forename: H
authors.initials: H
authors.lastname: San
authors.forename: M
authors.initials: M
authors.lastname: Paul
authors.forename: R C
authors.initials: RC
authors.lastname: Webb
authors.forename: E G
authors.initials: EG
authors.lastname: Nabel
mesh_terms: D000803:Angiotensin I / Q000494:pharmacology; D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D001158:Arteries / Q000502:physiology*; D002478:Cells, Cultured; D019332:Endothelin-1; D016232:Endothelins / Q000235:genetics*; D015870:Gene Expression; D006801:Humans; D066298:In Vitro Techniques; D009131:Muscle, Smooth, Vascular / Q000502:physiology*; D011498:Protein Precursors / Q000235:genetics*; D011499:Protein Processing, Post-Translational; D051381:Rats; D013552:Swine; D014162:Transfection; D014661:Vasoconstriction / Q000187:drug effects
chemical_list: D019332:Endothelin-1; D016232:Endothelins; D011498:Protein Precursors; D000804:Angiotensin II; D000803:Angiotensin I