Intima of Patients With Hypertension

Endothelin-1 is a potent vasoconstrictor produced by vascular endothelial cells. A recently cloned endothelin-1selective 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 Endothelin (ET) was initially identified in porcine vascular endothelial cells as a potent vasoconstrictor peptide with 21 amino acid residues. Cloning and sequencing of ET genes revealed three isopeptides, ET-1, ET-2, and ET-3, that have subsequently been found in a wide variety of vascular and nonvascular tissues.The discovery of three isopeptides and their different biologic activities raised the possibility that there were multiple ET receptor subtypes. The expression cloning of two ET receptors, the ETA and ETB receptors, has recently been reported. Both receptors contain seven putative transmembrane domains, similar to other G protein-coupled receptors, but these two ET receptors are functionally distinct. The rank order of binding to the ETA receptor is ET-1> ET-2 > > ET-3,whereas that for the ETB receptor is ET-l = ET-2=ET-3.Northern blotting has shown that ET receptor mRNAs are expressed in various organs and tissues including the aorta, heart, lungs, kidneys, and brain.However, the precise distribution of these receptors at the cellular level remains unclear. Proliferation of smooth muscle cells (SMCs) is a key feature of several pathogenic processes, including atherosclerosis, the vessel wall response to hypertension, Received May 4, 1993; accepted in revised form November 29, 1993. From the Third Division (K.H., H.F., K.D., T.I., S.O., S.S.) and Second Division (K.H., K.N.), Department of Internal Medicine, Faculty of Medicine, Kyoto University, and Kyoto Women's University (T.F.) (Japan). Correspondence to Hisayoshi Fujiwara, MD, Third Division, Department of Internal Medicine, Faculty of Medicine, Kyoto University, 54 Kawara-cho Shogoin, Sakyo-ku, Kyoto 606, Japan. 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-a-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. (Hypertension. 1994^3^88-293.)