Endothelin-1-selective receptor in the arterial intima of patients with hypertension

Endothelin-1 is a potent vasoconstrictor produced by vascular endothelial cells. A recently cloned endothelin-1-selective receptor, the endothelin-A receptor, mediates the vasoconstrictive action of endothelin-1. Because endothelin-1 also possesses mitogenic properties, it may play a role in regulating the proliferation of intimal smooth muscle cells. In this study, we analyzed the expression of endothelin-A receptor gene in the thickened arterial intima of patients with hypertension. Internal mammary artery specimens obtained from 12 patients undergoing cardiovascular surgery were subjected to in situ hybridization using a digoxigenin-labeled cRNA probe. High, homogeneous signals of endothelin-A receptor mRNA were observed in the medial smooth muscle cells of all vessels examined but not in the endothelial cells. Patients with hypertension displayed more severe intimal thickening than those without hypertension. Immunohistochemical analysis suggested that almost all of the intimal proliferative cells originated from smooth muscle cells. In contrast to media, endothelin-A receptor mRNA signals in intimal smooth muscle cells were low and heterogeneous. In the thickened arterial intima of hypertensive patients, the signals were detected just beneath the luminal endothelium but not deep in the intimal smooth muscle cell layer. By contrast, staining with anti-alpha-smooth muscle actin antibody was more intense in the deep layer than in the subendothelium. These findings suggest that the modulation of endothelin-A receptor gene expression in smooth muscle cells differs between the intima and media. Its regulated expression in intimal smooth muscle cells might affect the proliferative activity of these cells in patients with hypertension.