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

Mario Boehm; Xuefei Tian; Yuqiang Mao; Kenzo Ichimura; Melanie J Dufva; Khadem Ali; Svenja Dannewitz Prosseda; Yiwei Shi; Kazuya Kuramoto; Sushma Reddy; Vitaly O Kheyfets; Ross J Metzger; Edda Spiekerkoetter

doi:10.1093/cvr/cvz310

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

Cardiovasc Res. 2020 Aug 1;116(10):1700-1709. doi: 10.1093/cvr/cvz310.

Authors

Mario Boehm^{1

2

3}, Xuefei Tian^{1

2}, Yuqiang Mao^{1

2

4}, Kenzo Ichimura^{1

2}, Melanie J Dufva^{5

6}, Khadem Ali^{1

2}, Svenja Dannewitz Prosseda^{1

2}, Yiwei Shi^{1

2}, Kazuya Kuramoto^{1

2}, Sushma Reddy^{7

8}, Vitaly O Kheyfets^{5

6}, Ross J Metzger^{2

7}, Edda Spiekerkoetter^{1

2

8}

Affiliations

¹ Division of Pulmonary and Critical Care Medicine, Department of Medicine, Stanford University, 300 Pasteur Drive, Grand Bld Rm S126B, Stanford, CA 94305, USA.
² Vera Moulton Wall Center for Pulmonary Vascular Disease, Stanford School of Medicine, Stanford University, Stanford, CA, USA.
³ Department of Internal Medicine, Universities of Giessen and Marburg Lung Center (UGMLC), Justus-Liebig University Giessen, German Center for Lung Research (DZL), Giessen, Germany.
⁴ Department of Thoracic Surgery, Shengjing Hospital, China Medical University, Shenyang, China.
⁵ Department of Bioengineering, University of Colorado Denver, Denver, CO, USA.
⁶ Section of Cardiology, Department of Pediatrics, Children's Hospital Colorado, Denver, CO, USA.
⁷ Division of Cardiology, Department of Pediatrics, Stanford University, Stanford, CA, USA.
⁸ Cardiovascular Institute, Stanford University, Stanford, CA, USA.

Abstract

Aims: The temporal sequence of events underlying functional right ventricular (RV) recovery after improvement of pulmonary hypertension-associated pressure overload is unknown. We sought to establish a novel mouse model of gradual RV recovery from pressure overload and use it to delineate RV reverse-remodelling events.

Methods and results: Surgical pulmonary artery banding (PAB) around a 26-G needle induced RV dysfunction with increased RV pressures, reduced exercise capacity and caused liver congestion, hypertrophic, fibrotic, and vascular myocardial remodelling 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 remodelling were established-initiated recovery of RV function (cardiac output and exercise capacity) along with rapid normalization in RV hypertrophy (RV/left ventricular + S and cardiomyocyte area) and RV pressures (right ventricular systolic pressure). RV fibrotic (collagen, elastic fibres, and vimentin+ fibroblasts) and vascular (capillary density) remodelling were equally reversible; however, reversal occurred at a later timepoint after de-PAB, when RV function was already completely restored. Microarray gene expression (ClariomS, Thermo Fisher Scientific, Waltham, MA, USA) along with gene ontology analyses in RV tissues revealed growth factors, immune modulators, and apoptosis mediators as major cellular components underlying functional RV recovery.

Conclusion: 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-remodelling events.

Keywords: Fibrosis; Pulmonary hypertension; Recovery; Right ventricle.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Animals
Arterial Pressure
Disease Models, Animal
Exercise Tolerance
Fibroblasts / metabolism
Fibroblasts / pathology
Fibrosis
Hypertrophy, Right Ventricular / etiology
Hypertrophy, Right Ventricular / metabolism
Hypertrophy, Right Ventricular / pathology
Hypertrophy, Right Ventricular / physiopathology*
Male
Mice, Inbred C57BL
Myocardium / metabolism
Myocardium / pathology
Pulmonary Arterial Hypertension / etiology
Pulmonary Arterial Hypertension / physiopathology
Pulmonary Artery / physiopathology
Pulmonary Artery / surgery*
Recovery of Function
Suture Techniques
Time Factors
Ventricular Dysfunction, Right / etiology
Ventricular Dysfunction, Right / metabolism
Ventricular Dysfunction, Right / pathology
Ventricular Dysfunction, Right / physiopathology*
Ventricular Function, Right*
Ventricular Remodeling*

Abstract

Publication types

MeSH terms

Grants and funding