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 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.