Am. J. Respir. Crit. Care Med., Volume 165, Number 3, February 2002, 398-405

ET_A and ET_B Receptors Modulate the Proliferation of Human Pulmonary Artery Smooth Muscle Cells

NEIL DAVIE, STEPHEN J. HALEEN, PAUL D. UPTON, JULIA M. POLAK, MAGDI H. YACOUB, NICHOLAS W. MORRELL, and JOHN WHARTON

Section on Clinical Pharmacology, Departments of Histochemistry and Cardiothoracic Surgery, Faculty of Medicine, Imperial College, London; Department of Medicine, University of Cambridge, Addenbrooke's Hospital, Cambridge, United Kingdom; Pfizer Global Research and Development, Ann Arbor, Michigan, United States

We determined the distribution of ET_A and ET_B receptors in pulmonary arteries from pulmonary hypertensive patients and control subjects, using in vitro autoradiography, and investigated their role in mediating the proliferative effects of endothelin-1 (ET-1) on distal human pulmonary artery smooth muscle cells (PASMCs). Distal arteries possessed more medial [¹²⁵I]-ET-1 binding sites (105 ± 10 versus 45 ± 6 amol/mm²; p < 0.001) and a greater proportion of ET_B receptors than proximal arteries (36 ± 3% versus 3 ± 1%; p < 0.001). Receptor density in distal arteries and lung parenchyma was twofold greater (p < 0.05) in pulmonary hypertensive patients than in control subjects. ET-1 (10⁹-10⁷ mol/L) stimulated DNA synthesis (147 ± 10% of control subjects; p < 0.05) and attenuated the antiproliferative action of cicaprost and forskolin on PASMCs, these effects being mediated via ET_A and ET_B receptors. Serum-stimulated proliferation was attenuated by inhibiting either endogenous ET-1 release with phosphoramidon (10⁵ mol/L) or its action with PD145065 (10⁵ mol/L). Cicaprost (10¹⁰-10⁷ mol/L) inhibited ET-1 release from PASMCs (49 ± 16% of control after 24 h; p < 0.001) and increased intracellular cAMP levels, whereas ET_B receptor stimulation selectively reduced cAMP levels. In conclusion, ET_A and ET_B receptors are differentially distributed in human pulmonary arteries. Both receptors promote the proliferation of PASMCs in vitro and may contribute to vascular remodeling in pulmonary hypertension.

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