What does this research mean for the field?

ETA and ETB receptors are differentially distributed in human pulmonary arteries, exhibit increased density in patients with pulmonary hypertension, and both mediate the proliferation of pulmonary artery smooth muscle cells. Novelty: ClaimNovelty.INCREMENTAL. Consensus alignment: ConsensusAlignment.NEUTRAL.

February 1, 2002

ETA and ETB Receptors Modulate the Proliferation of Human Pulmonary Artery Smooth Muscle Cells

Structured PICO

Population

Pulmonary arteries from pulmonary hypertensive patients and control subjects, and distal human pulmonary artery smooth muscle cells (PASMCs)

Intervention

Endothelin-1 (ET-1) (10(-9)-10(-7) mol/L), cicaprost, forskolin, phosphoramidon, PD145065

Comparator

Control subjects (for tissue) and untreated cells (for in vitro assays)

Outcome

Distribution of ET(A) and ET(B) receptors and DNA synthesis/proliferation of PASMCssurrogate

ET(A) and ET(B) receptors are differentially distributed in human pulmonary arteries and both promote the proliferation of PASMCs in vitro, suggesting a role in vascular remodeling in pulmonary hypertension.

Abstract

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 (125)I-ET-1 binding sites (105 +/- 10 versus 45 +/- 6 amol/mm(2); 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 (10(-9)-10(-7) 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 (10(-5) mol/L) or its action with PD145065 (10(-5) mol/L). Cicaprost (10(-10)-10(-7) 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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