Endothelin ET A receptors predominate in chronic thromboembolic pulmonary hypertension

Abstract

AimsEndothelin-1 levels are raised in chronic thromboembolic pulmonary hypertension. Our aim in this study was to identify the presence of endothelin receptors in patients with CTEPH by analysing tissue removed at pulmonary endarterectomy.Main methodsPulmonary endarterectomy tissue cross-sections were analysed using autoradiography with [125I]-ET-1 using ligands selective for ETA or ETB to determine sub-type distribution. The precise cellular localisation of ETA and ETB receptors was determined using selective antisera to both sub-types and compared with haematoxylin and eosin, Elastic Van Gieson and smooth muscle actin labelled sections.Key findingsTwo patterns of ET-1 binding were found. In sections with frequent recanalised channels, ET-1 bound to the smooth muscle cells surrounding the channels. In sections where there was less organised thrombus with no obvious re-canalisation, minimal ET-1 binding was observed. Some contractile type smooth muscle cells not associated with recanalised channels and diffusely spread throughout the PEA material were associated with ET receptor antibody binding on immunohistochemistry. There was a greater expression of the ETA receptor type in the specimens.SignificanceThe presence of ET-1 receptors in the chronic thrombus in proximal CTEPH suggests ET-1 could act not only on the distal vasculopathy in the unobstructed vessels but may also stimulate smooth muscle cell proliferation within chronic clot. The abundance of ET receptors within the tissue provides evidence that the ET pathway is involved in the pathology of chronic thrombus reorganisation leading to CTEPH providing a rationale for the repurposing of ET receptor antagonists in the treatment of this condition.

Pulmonary microvascular remodeling in chronic thrombo-embolic pulmonary hypertension

“…Moreover, ET B receptor blockade attenuated the contraction to ET-1 in the presence of ET A receptor blockade, but it had no effect in pulmonary small arteries from animals with CTEPH. These data are in accordance with the increased ET A receptor expression in pulmonary endarterectomy tissues (53) and in the lungs of swine with CTEPH (39), as well as with the increased ET A /ET B ratio observed in the present study. The latter was, however, primarily because of a decrease in ET B mRNA, which contrasts with another study in a different CTEPH swine model that shows an increased ET B mRNA expression in the unobstructed areas of the lungs (39).…”

Chronic Thromboembolic Pulmonary Hypertension – What Have We Learned From Large Animal Models

“…This decreased sensitivity to ET was accompanied by an increased ET A but decreased ET B contribution to ETinduced vasoconstriction. These data were consistent with an increased ET A /ET B gene expression ratio in lung tissue (56) as well as with the increased ET A receptor expression in human pulmonary endarterectomy tissues (85) and in the lungs of swine with CTEPH (47,50). These data from large animal models and humans suggest that ET signaling is altered in the pulmonary microvasculature in CTEPH.…”

The pathophysiology of chronic thromboembolic pulmonary hypertension

“…Levels of endothelin (ET)-1 are elevated in patients with CTEPH and in animal models of the condition [75][76][77][78][79]. Recent evidence suggests a potential role for ET-1 in smooth muscle cell proliferation within the chronic clot in CTEPH and in small-vessel disease [80]. Levels of vascular endothelial growth factor A are significantly decreased after PEA in patients with CTEPH [81].…”