Pulmonary microvascular remodeling in chronic thrombo-embolic pulmonary hypertension

Abstract

Pulmonary vascular remodeling in pulmonary arterial hypertension involves perturbations in the nitric oxide (NO) and endothelin-1 (ET-1) pathways. However, the implications of pulmonary vascular remodeling and these pathways remain unclear in chronic thrombo-embolic pulmonary hypertension (CTEPH). The objective of the present study was to characterize changes in microvascular morphology and function, focussing on the ET-1 and NO pathways, in a CTEPH swine model. Swine were chronically instrumented and received up to five pulmonary embolizations by microsphere infusion, whereas endothelial dysfunction was induced by daily administration of the endothelial NO synthase inhibitor Nω-nitro-l-arginine methyl ester until 2 wk before the end of study. Swine were subjected to exercise, and the pulmonary vasculature was investigated by hemodynamic, histological, quantitative PCR, and myograph experiments. In swine with CTEPH, the increased right-ventricular afterload, decreased cardiac index, and mild ventilation-perfusion-mismatch were exacerbated during exercise. Pulmonary microvascular remodeling was evidenced by increased muscularization, which was accompanied by an increased maximal vasoconstriction. Although ET-1-induced vasoconstriction was increased in CTEPH pulmonary small arteries, the ET-1 sensitivity was decreased. Moreover, the contribution of the ETA receptor to ET-1 vasoconstriction was increased, whereas the contribution of the ETB receptor was decreased and the contribution of Rho-kinase was lost. A reduction in endogenous NO production was compensated in part by a decreased phosphodiesterase 5 (PDE5) activity resulting in an apparent increased NO sensitivity in CTEPH pulmonary small arteries. These findings suggest that pulmonary microvascular remodeling with a reduced activity of PDE5 and Rho-kinase may contribute to the lack of therapeutic efficacy of PDE5 inhibitors and Rho-kinase inhibitors in CTEPH.

Cardiac remodelling in a swine model of chronic thromboembolic pulmonary hypertension: comparison of right vs. left ventricle

“…Activation of the TGF-β pathway was further confirmed by the increase in expression of its downstream target PAI-1. Both activation of the TGF-β pathway and increased circulating levels of endothelin, as previously shown to be present in our porcine CTEPH model (Stam et al 2018b), can result in activation of the Rho-kinase pathway (Zeidan et al 2014;Shimizu & Liao, 2016;Tsai et al 2017). Indeed, ROCK2 expression was up-regulated in CTEPH swine and showed a strong inverse correlation with RV-PA coupling.…”

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

“…It is difficult to distinguish between an increase in resistance due to recurrent embolizations and an increase in resistance due to microvascular remodeling even in animal models. Nevertheless, pulmonary vascular resistance continued to increase after cessation of the embolization procedures in our swine model, which suggest persistent remodeling of the distal vasculature (37,56). Even after cessation of the eNOS inhibitor, which may also have contributed to a higher pulmonary vascular resistance by increasing microvascular tone, the high pulmonary pressure and resistance persisted (37,56).…”

“…In the porcine studies from our laboratory, CTEPH was induced with multiple (up to 5) embolizations using an average of 9,000 microspheres of 600-710 µm in diameter per embolization procedure, hence 45,000 microspheres in total (37,55,56). This number is much higher than the number of order 3 and 4 pulmonary small arteries present in the porcine lung and hence should be able to obstruct a sufficiently large part of the pulmonary vasculature.…”

Recent advances in our understanding of the mechanisms of lung alveolarization and bronchopulmonary dysplasia

“…Several recent studies have extended existing work on interventional strategies to promote lung alveolarization under pathological conditions. Phosphodiesterase 5 (PDE) continues to receive attention as a potential drug target in the management of pulmonary hypertension (205,281,409,443,545), cardiac remodeling, and alveolar simplification that result from oxygen support. One recent study applied the PDE5 inhibitor sildenafil to rats in the room air recovery period after exposure to hyperoxia for the first two weeks of postnatal life (460), where "delayed" sildenafil therapy improved right ventricular hypertrophy (pulmonary hemodynamics were not addressed), but not alveolar simplification.…”