Fibroblasts and the extracellular matrix in right ventricular disease

Abstract

Right ventricular failure predicts adverse outcome in patients with pulmonary hypertension (PH), and in subjects with left ventricular heart failure and is associated with interstitial fibrosis. This review manuscript discusses the cellular effectors and molecular mechanisms implicated in right ventricular fibrosis. The right ventricular interstitium contains vascular cells, fibroblasts, and immune cells, enmeshed in a collagen-based matrix. Right ventricular pressure overload in PH is associated with the expansion of the fibroblast population, myofibroblast activation, and secretion of extracellular matrix proteins. Mechanosensitive transduction of adrenergic signalling and stimulation of the renin-angiotensin-aldosterone cascade trigger the activation of right ventricular fibroblasts. Inflammatory cytokines and chemokines may contribute to expansion and activation of macrophages that may serve as a source of fibrogenic growth factors, such as transforming growth factor (TGF)-β. Endothelin-1, TGF-βs, and matricellular proteins co-operate to activate cardiac myofibroblasts, and promote synthesis of matrix proteins. In comparison with the left ventricle, the RV tolerates well volume overload and ischemia; whether the right ventricular interstitial cells and matrix are implicated in these favourable responses remains unknown. Expansion of fibroblasts and extracellular matrix protein deposition are prominent features of arrhythmogenic right ventricular cardiomyopathies and may be implicated in the pathogenesis of arrhythmic events. Prevailing conceptual paradigms on right ventricular remodelling are based on extrapolation of findings in models of left ventricular injury. Considering the unique embryologic, morphological, and physiologic properties of the RV and the clinical significance of right ventricular failure, there is a need further to dissect RV-specific mechanisms of fibrosis and interstitial remodelling.

Keywords: Arhhythmogenenic right ventricular cardiomyopathy; Cardiac fibrosis; Extracellular matrix; Pulmonary hypertension; Right ventricular failure.

Figure 1

The right ventricular interstitium. (A) The adult mammalian myocardium is comprised of cardiomyocytes, abundant microvessels (EC, endothelial cells) and a highly cellular interstitium that contains large numbers of fibroblasts (F), pericytes (P) and smaller populations of macrophages (Ma) and other immune cells, enmeshed into a collagen-based matrix. Although systematic comparison of the cellular composition and matrix content between the right and the left ventricular myocardium has not been performed, the interstitium of the RV and the left ventricle have similar morphological characteristics. (B and C) Representative images show staining with picrosirius red of sections from the right ventricular free wall (B, RV) and the left ventricular free wall (C, LV) in adult mouse hearts, in order to identify the collagen network. The epimysial collagen surrounds the organ (arrow); each cardiomyocyte is associated with a thin rim of endomysial collagen (arrowhead). (D, E) Dual fluorescence for wheat germ agglutinin outlines the cardiomyocytes in the mouse right ventricle (D, RV) and in the left ventricular free wall (E, LV). Experimental studies in adult rats have suggested that due to the lower baseline pressure load and the smaller size of right ventricular cardiomyocytes, the RV exhibits a higher relative collagen content, when compared with the left ventricle and the interventricular septum. (F) Immunohistochemical staining for the macrophage-specific antibody Mac2 identified a resident macrophage population in the right ventricular wall (arrows).

Figure 2

Cell biological effectors of fibrosis in the pressure-overloaded RV. Based on insights from lineage tracing experiments in models of left ventricular pressure overload, activated myofibroblasts are predominantly derived from resident populations. Endothelial cells, pericytes, epicardial epithelial cells, and circulating fibroblast progenitors may also play contributory roles. Vascular cells, stressed cardiomyocytes, resident, and recruited macrophages may play an important role in activation of resident fibroblast population in the pressure-overloaded myocardium.

Figure 3

Molecular signals implicated in fibroblast activation in the pressure-overloaded RV. Right ventricular pressure overload transduces mechanosensitive signalling in cardiomyocytes (CM), fibroblasts (F), vascular endothelial cells (EC), and macrophages (Ma), stimulating neurohumoral pathways and activating reactive oxygen species (ROS) generation. Activation of the RAAS pathway, adrenergic signalling, and oxidative stress stimulate fibroblast expansion and triggers synthesis of extracellular matrix proteins. Angiotensin II and aldosterone may also induce an inflammatory and fibrogenic program in endothelial cells, stimulating expression of endothelin-1 (ET-1), and synthesis of chemokines, and triggering recruitment of monocytes (Mo). Activated macrophages secrete transforming growth factor (TGF)-β and other growth factors in the cardiac interstitium. Enrichment of the extracellular matrix though the deposition of matricellular proteins regulates activation of growth factor signalling. TGF-β exerts potent matrix-preserving actions by promoting myofibroblast transdifferentiation, by stimulating synthesis of matrix proteins, and by inducing expression of antiproteases.