EXPRESSION OF A RECOMBINANT PREPROENDOTHELIN-1 GENE IN ARTERIES STIMULATES VASCULAR CONTRACTILITY

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 e ffects of ET-1 gene expression were investigated using gene-transfer m ethods on porcine vascular cells in vitro and porcine arteries in vivo . Transfection of vascular cells with a vector encoding for human prep roendothelin-l cDNA (pVR-ppET) resulted in significant increases in ac tive ET-1 levels in culture supernatant compared with nontransfected c ells (P < 0.05). This supernatant contracted rat aortic strips at conc entrations 10-fold lower than synthetic ET-1 protein, which was inhibi ted by the ET-A receptor antagonist BQ-123. Transfection of pVR-ppET i nto pig iliofemoral arteries resulted in an increase in contractile re sponses 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 recombin ant ET-1 gene in vivo augments vascular contractility due to an increa sed sensitivity to angiotensin I, suggesting a role for ET-1 in the pa thogenesis of cardiovascular diseases.