Dual ETA/ETB blockade with macitentan improves both vascular remodeling and angiogenesis in pulmonary arterial hypertension

Valerie Nadeau; Francois Potus; Olivier Boucherat; Renee Paradis; Eve Tremblay; Marc Iglarz; Roxane Paulin; Sebastien Bonnet; Steeve Provencher

doi:10.1177/2045893217741429

Dual ET_A/ET_B blockade with macitentan improves both vascular remodeling and angiogenesis in pulmonary arterial hypertension

Pulm Circ. 2018 Jan-Mar;8(1):2045893217741429. doi: 10.1177/2045893217741429. Epub 2017 Oct 24.

Authors

Valerie Nadeau^{1

2}, Francois Potus^{1

2}, Olivier Boucherat^{1

2

3}, Renee Paradis^{1

2}, Eve Tremblay^{1

2}, Marc Iglarz⁴, Roxane Paulin^{1

2

3}, Sebastien Bonnet^{1

2

3}, Steeve Provencher^{1

2

3}

Affiliations

¹ 1 Pulmonary Hypertension Research Group ( http://www.hypertensionarteriellepulmonaire.ca ).
² 2 Institut universitaire de cardiologie et de pneumologie de Québec Research Center, Laval University, Quebec City, Canada.
³ 3 Department of Medicine, Laval University, Quebec, Canada.
⁴ 4 Drug Discovery Department, Actelion Pharmaceuticals Ltd., Allschwil, Switzerland.

Abstract

Dysregulated metabolism and rarefaction of the capillary network play a critical role in pulmonary arterial hypertension (PAH) etiology. They are associated with a decrease in perfusion of the lungs, skeletal muscles, and right ventricle (RV). Previous studies suggested that endothelin-1 (ET-1) modulates both metabolism and angiogenesis. We hypothesized that dual ET_A/ET_B receptors blockade improves PAH by improving cell metabolism and promoting angiogenesis. Five weeks after disease induction, Sugen/hypoxic rats presented severe PAH with pulmonary artery (PA) remodeling, RV hypertrophy and capillary rarefaction in the lungs, RV, and skeletal muscles (microCT angiogram, lectin perfusion, CD31 staining). Two-week treatment with dual ET_A/ET_B receptors antagonist macitentan (30 mg/kg/d) significantly improved pulmonary hemodynamics, PA vascular remodeling, and RV function and hypertrophy compared to vehicle-treated animals (all P = 0.05). Moreover, macitentan markedly increased lung, RV and quadriceps perfusion, and microvascular density (all P = 0.05). In vitro, these effects were associated with increases in oxidative phosphorylation (oxPhox) and markedly reduced cell proliferation of PAH-PA smooth muscle cells (PASMCs) treated with macitentan without affecting apoptosis. While macitentan did not affect oxPhox, proliferation, and apoptosis of PAH-PA endothelial cells (PAECs), it significantly improved their angiogenic capacity (tube formation assay). Exposure of control PASMC and PAEC to ET-1 fully mimicked the PAH cells phenotype, thus confirming that ET-1 is implicated in both metabolism and angiogenesis abnormalities in PAH. Dual ET_A/ET_B receptor blockade improved the metabolic changes involved in PAH-PASMCs' proliferation and the angiogenic capacity of PAH-PAEC leading to an increased capillary density in lungs, RV, and skeletal muscles.

Keywords: Sugen/hypoxia; Warburg effect; angiogenesis; endothelin; endothelin receptor blockade; macitentan; pulmonary hypertension.