Endothelin A receptor blockade improves regression of flow-induced pulmonary vasculopathy in piglets

Objectives

In patients with chronic thromboembolic pulmonary hypertension, high flow in unobstructed lung regions may induce small-vessel damage responsible for persistent pulmonary hypertension after pulmonary thromboendarterectomy. In piglets, closure of an experimental aortopulmonary shunt reverses the flow-induced vascular lesions and diminishes the elevated levels of messenger RNA (mRNA) expression for endothelin-1 and endothelin receptor A (ETA). We wanted to study the effect of the ETA antagonist TBC 3711 on reversal of flow-induced pulmonary vascular lesions.

Methods

Twenty piglets were studied. In 15 piglets, pulmonary vasculopathy was induced by creating an aortopulmonary shunt. After 5 weeks of shunting, some animals were studied (n = 5); others underwent shunt closure for 1 week with (n = 5) or without (n = 5) TBC3711 treatment. Anti-ETA treatment started 1 week before and ended 1 week after the shunt closure. The controls were sham-operated animals (n = 5).

Results

High blood flow led to medial hypertrophy of the distal pulmonary arteries (54.9% ± 1.3% vs 35.3% ± 0.9%; P < .0001) by stimulating smooth muscle cell proliferation (proliferating cell nuclear antigen) and increased the expression of endothelin-1, ETA or endothelin receptor type A or endothelin receptor A, angiopoietin 1, and Tie2 (real-time polymerase chain reaction). One week after shunt closure, gene expression levels were normal and smooth muscle cells showed increased apoptosis (terminal deoxynucleotidyl transferase–mediated dUTP nick end labeling) without proliferation. However, pulmonary artery wall thickness returned to control values only in the group given TBC3711 (33.2% ± 8% with and 50.3% ± 1.3% without; P < .05).

Conclusions

Anti-ETA therapy accelerated the reversal of flow-induced pulmonary arterial disease after flow correction. In patients with chronic thromboembolic pulmonary hypertension and severe distal pulmonary vasculopathy, anti-ETA agents may prove useful for preventing persistent pulmonary hypertension after pulmonary thromboendarterectomy.

CTSNet classification: 9, 11.4, 26.6, 29

Abbreviations and Acronyms: Ang-1, angiopoietin-1, CTEPH, chronic thromboembolic pulmonary hypertension, ET-1, endothelin-1, ETA, endothelin receptor type A, ETB, endothelin receptor type B, mRNA, messenger RNA, PA-SMC, pulmonary artery smooth muscle cell, PCNA, proliferating cell nuclear antigen, PH, pulmonary hypertension, PTE, pulmonary thromboendarterectomie, PVR, pulmonary vascular resistance, RT-PCR, real-time polymerase chain reaction, TUNEL, terminal deoxynucleotidyl transferase–mediated dUTP nick end labeling