Delineating the molecular and histological events that govern right ventricular recovery using a novel mouse model of pulmonary artery de-banding

Abstract

AIMS The temporal sequence of events underlying functional right ventricular (RV) recovery after improvement of pulmonary hypertension-associated pressure overload are unknown. We sought to establish a novel mouse model of gradual RV recovery from pressure overload and use it to delineate RV reverse-remodeling events. METHODS AND RESULTS Surgical pulmonary artery banding (PAB) around a 26G needle induced RV dysfunction with increased RV pressures, reduced exercise capacity and caused liver congestion, hypertrophic, fibrotic and vascular myocardial remodeling within 5 weeks of chronic RV pressure overload in mice. Gradual reduction of the afterload burden through PA band absorption (de-PAB) - after RV dysfunction and structural remodeling were established - initiated recovery of RV function (cardiac output, exercise capacity) along with rapid normalization in RV hypertrophy (RV/LV+S, cardiomyocyte area) and RV pressures (RVSP). RV fibrotic (collagen, elastic fibers, vimentin+ fibroblasts) and vascular (capillary density) remodeling were equally reversible, however reversal occurred at a later time-point after de-PAB, when RV function was already completely restored. Microarray gene expression (ClariomS, Thermo Fisher) along with gene ontology analyses in RV tissues revealed growth factors, immune modulators and apoptosis mediators as major cellular components underlying functional RV recovery. CONCLUSIONS We established a novel gradual de-PAB mouse model and used it to demonstrate that established pulmonary hypertension-associated RV dysfunction is fully reversible. Mechanistically, we link functional RV improvement to hypertrophic normalization that precedes fibrotic and vascular reverse-remodeling events. Translational Perspective The right ventricle (RV) in pulmonary arterial hypertension possesses a remarkable ability to recover after lung transplantation. Yet, some transplant centers prefer a heart-lung instead of lung transplantation when the RV function is severely impaired because knowledge is lacking whether fibrotic and vascular myocardial remodeling are completely reversible once the increased afterload burden is relieved. We have developed a mouse model to study gradual unloading of the RV and identified key molecular components and the timing of RV reverse-remodeling events with the ultimate goal to understand the RV recovery process and identify ways how to support the RV during recovery.

Animal models of pulmonary hypertension: Getting to the heart of the problem

“…In addition to reductions in forced high intensity exercise (Piao et al, 2012) and voluntary low intensity exercise (Borgdorff et al, 2012(Borgdorff et al, , 2013b, inactivity, reduced grooming, dyspnea/tachypnea, poor peripheral circulation, ascites and pleural/pericardial effusions have been reported, culminating in a high mortality rate (LekanneDeprez et al, 1998;Schou et al, 2007;Borgdorff et al, 2013bBorgdorff et al, , 2015b. These pathological changes have also been replicated in mice (Urashima et al, 2008;Kapur et al, 2013;Egemnazarov et al, 2015;Boehm et al, 2017Boehm et al, , 2020.…”

Treatment Targets for Right Ventricular Dysfunction in Pulmonary Arterial Hypertension

“…However, multiple preclinical drug studies show reduction in RV fibrosis is associated with improved RV function, but all occur in the setting of reduced afterload ( 65 , 66 , 67 , 68 , 69 ). Furthermore, a novel pulmonary artery debanding mouse model shows that, after pulmonary artery band resorption, RV function is restored with normalization of cardiomyocyte size and reversal of fibrosis ( 70 ).…”

Targeted Proteomics of Right Heart Adaptation to Pulmonary Arterial Hypertension

“…rats with monocrotaline-induced PH, rabbits with shunt flow-induced PH) have shown that exogenous HGF or Hgf gene transfection reduced the development of PH, which was associated with less marked right heart hypertrophy and lower inflammatory profiles than shams (27–30). However, the timely and direct effect of the HGF/c-Met axis activation in the right heart remains to be elucidated, and here the PAB model might be of particular value to explore the dynamic changes in plasma and tissue HGF expression over time and potential reversibility with de-banding (10).…”

“…Chronic RV pressure overload was induced in 10-14 week-old male C57BL/6 mice ( Supplementary Methods ) (10). Anesthetized animals underwent thoracotomy, 6-0 silk sutures were used to band the main pulmonary artery (PA), and one-week post-surgery a peak pressure gradient >15 mmHg was confirmed across the band by echocardiography (GE Vivid 7).…”