The upregulation of endothelin and its receptors in porcine coronary arteries in a double balloon injury model of restenosis

Endothelin, a potent vasoconstrictor, mitogen, and stimulant of collagen sy nthesis, is reported to be increased after vascular injury. We tested the h ypothesis that tissue endothelin levels and its receptor expression are inc reased following double balloon injury in a porcine coronary artery model o f restenosis. Male miniature swine maintained on a hyperlipidemic diet unde rwent oversized balloon injury to both the proximal right coronary artery a nd left circumflex coronary artery. Two weeks following the initial injury, the arteries were repeat injured at the same site and subsequently harvest ed four weeks later. Proximal balloon injured (BI) and distal non-balloon-i njured (NBI) segments from the same artery were collected. Tissue endotheli n-1 (ET-1) levels were measured by ELISA. Endothelin receptors were assayed by radioligand binding using I-125-ET-1 and also immunolabeling. Tissue en dothelin levels were 4-5 fold greater in BI arteries as compared to NBI. Th ere was a significant increase in tissue ET-1 levels and endothelin recepto r binding following double balloon injury relative to NBI control arteries. Western blots showed an increased expression of ETA receptor protein in in jured vessels compared to non-injured arteries. Immunohistochemistry using an ETA receptor specific antibody confirmed increased receptor density foll owing balloon injury. Thus, in an in vivo double balloon injury model for c oronary artery restenosis, the response to vascular injury is increased tis sue ET-1 content and upregulation of ETA receptor density associated with i ncreased receptor protein.