Endothelial deletion of Ino80 disrupts coronary angiogenesis and causes congenital heart disease

Abstract

During development, the formation of a mature, well-functioning heart requires transformation of the ventricular wall from a loose trabecular network into a dense compact myocardium at mid-gestation. Failure to compact is associated in humans with congenital diseases such as left ventricular non-compaction (LVNC). The mechanisms regulating myocardial compaction are however still poorly understood. Here, we show that deletion of the Ino80 chromatin remodeler in vascular endothelial cells prevents ventricular compaction in the developing mouse heart. This correlates with defective coronary vascularization, and specific deletion of Ino80 in the two major coronary progenitor tissues-sinus venosus and endocardium-causes intermediate phenotypes. In vitro, endothelial cells promote myocardial expansion independently of blood flow in an Ino80-dependent manner. Ino80 deletion increases the expression of E2F-activated genes and endothelial cell S-phase occupancy. Thus, Ino80 is essential for coronary angiogenesis and allows coronary vessels to support proper compaction of the heart wall.

Deletion of Sphingosine 1-Phosphate Receptor 1 in cardiomyocytes during development leads to abnormal ventricular conduction and fibrosis

“…Other mouse models of ventricular noncompaction have demonstrated non-uniform expression of Cx40 in the trabecular myocardium; specifically, disruption of some components of the Notch signaling pathway (combined deletion of cardiomyocyte Jagged1 and Jagged2, as well as endothelial overexpression of Manic Fringe) and endothelial-specific deletion of Ino80 led to the same Cx40 expression pattern that we observed [29,35]. This "intermediate myocardium" represents a margin between trabecular and compact myocardium, with cardiomyocytes that display trabecular morphology but express molecular markers of compact/non-trabecular myocardium.…”

“…However, Cx40 expression was not uniformly expressed in the trabecular myocardium of Mlc2a Cre/+ ; S1pr1 f/mutant hearts; trabecular myocardium closer to the thin compact wall expressed lower levels of Cx40 by immunostaining ( Figure 3D'). This Cx40 expression pattern has been noted in a subset of ventricular noncompaction models and has been termed "intermediate myocardium" [28,29]. We observed no significant differences in the immunostaining patterns for Connexin 43 (Cx43) or N-Cadherin (Supplemental Figure 2).…”

Defects in Trabecular Development Contribute to Left Ventricular Noncompaction

“…Mutations in the NKX2-5 gene have been identified in LVNC patients indicating a role for this important cardiac transcription factor in compaction [41,42]. In Nkx2-5 heterozygous mutant mice, noncompaction of the ventricular myocardium is observed in the apex suggesting a late compaction of the apical part, as previously suggested for the development of the coronary vasculature [36]. A similar phenotype is observed in 14-3-3ε -/mice that display abnormal coronary vasculature and ventricular noncompaction in the apical region of the heart [43].…”

“…A similar process takes place during neo-vascularization following myocardial infarction in the adult heart [34]. Epicardial-derived cells and cells from the sinus venosus also participate in building the coronary vasculature [35,36].…”

Reptiles as a Model System to Study Heart Development

“…The endocardium has important roles in regulating the contributions of the trabecular and compact components (D'Amato et al 2016;Del Monte-Nieto et al 2018). A recent systemic endothelial knockout of the chromatin remodeler Ino80 (Tie2Cre; Ino80 fl/fl) in mouse resulted in arguably the most reptile-like ventricular wall of any mouse model (Rhee et al 2018). In the human heart, an excessive amount of trabecular myocardium allows for the diagnosis of noncompaction cardiomyopathy (Finsterer et al 2017;Towbin and Jefferies 2017).…”