Increased endothelium activation and leakage do not promote diastolic dysfunction in mice fed with a high fat diet and treated with L-NAME

Coronary microvascular disease has been proposed to be responsible for heart failure with preserved ejection fraction (HFpEF) about 10 years ago. However, to date the role and phenotype of the coronary microvasculature has still been poorly considered and investigated in animal models of HFpEF. Objective To determine whether endothelial dysfunction participates in the development of diastolic dysfunction in mice fed with a high fat diet (HDF) and treated with L-NAME. Approach and Results At first, we thoroughly phenotyped the coronary microvasculature in this model in male, female and ovariectomized (OVX) female considering the sexual dimorphism associated with this disease. We found that both OVX and non OVX females but not males display increased endothelial activation, leakage, and arteriole constriction upon the HFD + L-NAME regimen while both male and OVX females but not non OVX females develop diastolic dysfunction. With the aim to investigate the role of endothelial dysfunction in the pathophysiology of diastolic dysfunction in OVX female mice, we used Cdon deficient mice. Indeed, we previously demonstrated that endothelium integrity, upon inflammatory conditions, is preserved in these mice. Both OVX Cdh5-Cre/ERT2-Cdon Flox/Flox (Cdon ECKO ) and Cdon Flox/Flox (Ctrl) female mice were fed with the HFD + L-NAME regimen to induced diastolic dysfunction. As expected, Cdon ECKO mice displayed improved endothelium integrity i.e. decreased endothelium permeability, decreased ICAM-1 expression and decreased infiltration of CD45+ leukocytes in comparison to control mice. However, Cdon ECKO mice displayed cardiac hypertrophy, cardiac fibrosis and increased end diastolic pressure just like control mice. Moreover, we found that cardiac inflammation does not participate in the pathophysiology of HFpEF either by treating OVX female mice with colchicine. Conclusion Altogether, the data presented in this paper demonstrate that neither endothelium permeability nor endothelial activation or inflammation do participate in the pathophysiology of diastolic dysfunction in mice exposed to HFD+L-NAME.