Adrenomedullin expression and growth inhibitory effects in distinct pulmonary artery smooth muscle cell subpopulations

The vasodilator peptide adrenomedullin is elevated in patients with pulmona ry hypertension and has been implicated in the inhibition of vascular remod eling. We questioned whether adrenomedullin is released by human pulmonary artery smooth muscle cells (PASMCs) and inhibits PASMC growth and release o f endothelin, a known smooth muscle cell mitogen. The majority of PASMCs is olated from proximal pulmonary arteries and all PASMCs from distal pulmonar y arteries released adrenomedullin, although at differing rates (mean, 177 +/- 28 and 62 +/- 11 fmol/10(5) cells/24 h, respectively). These cells were designated ADM(+). However, some proximal PASMC isolates did not release a drenomedullin, designated ADM(-). Northern blot analysis confirmed adrenome dullin expression in proximal ADM(+) but not ADM(-) isolates. ADM(-) and di stal ADM(+) PASMCs proliferated faster in serum than did proximal ADM(+) ce lls. Adrenomedullin potently and dose-dependently (mean EC50 = 2.2 +/- 0.5 nM) increased intracellular cyclic adenosine monophosphate (cAMP) in ADM(-) isolates via specific adrenomedullin receptors. In contrast, both adrenome dullin and calcitonin gene-related peptide modestly elevated cAMP in 50% of ADM(+) isolates. Adrenomedullin dose-dependently inhibited platelet-derive d growth factor-stimulated [H-3]thymidine incorporation and endothelin rele ase in ADM(-) cells but did not affect [H-3]thymidine uptake in ADM(+) isol ates. We conclude that distinct subpopulations of human PASMCs release and respond to adrenomedullin. The heterogeneity of adrenomedullin release and the inhibition of PASMC DNA synthesis and endothelin release suggest that a drenomedullin may function as a paracrine mediator in the inhibition of pul monary vascular remodeling.