Abstract
The homeostasis of heart and other organs relies on the appropriate provision of nutrients and functional specialization of the local vasculature. Here, we have used mouse genetics, imaging and cell biology approaches to investigate how homeostasis in the adult heart is controlled by endothelial EphB4 and its ligand ephrin-B2, which are known regulators of vascular morphogenesis and arteriovenous differentiation during development. We show that inducible and endothelial cell-specific inactivation of Ephb4 in adult mice is compatible with survival, but leads to rupturing of cardiac capillaries, cardiomyocyte hypertrophy, and pathological cardiac remodeling. In contrast, EphB4 is not required for integrity and homeostasis of capillaries in skeletal muscle. Our analysis of mutant mice and cultured endothelial cells shows that EphB4 controls the function of caveolae, cell-cell adhesion under mechanical stress and lipid transport. We propose that EphB4 maintains critical functional properties of the adult cardiac vasculature and thereby prevents dilated cardiomyopathy-like defects.
Highlights
Dilated cardiomyopathy (DCM) is a common and irreversible type of heart disease
EphB4 is expressed in large veins, whereas ephrin-B2 is restricted to arteries (Figure 1—figure supplement 1A,B)
EphB4 expression was strongly diminished in the coronaries of Cdh5CreERT2 Ephb4flox/flox (Ephb4DEC) hearts when compared to Cre-negative littermate controls (Figure 1—figure supplement 1D)
Summary
Dilated cardiomyopathy (DCM) is a common and irreversible type of heart disease. It is the third most common case of heart failure and the most frequent cause for heart transplantation (American Heart Association et al, 2006) with an estimated prevalence of 40 in 100.000 people (Manolio et al, 1992). Up to 80% of DCM patients present heart failure symptoms (Dec and Fuster, 1994). The disease first affects the left ventricle, where the muscle starts to remodel, leading to increased end-diastolic and end-systolic volumes (Mestroni et al, 2014). The heart is a highly vascularized organ and capillaries reside in close proximity to almost every cardiomyocyte with a cellular ratio between cardiomyocytes and endothelial cells (ECs) of 1:3
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