A novel murine model for endothelial dysfunction and Heart Failure with Preserved Ejection Fraction

Abstract

Heart Failure with Preserved Ejection Fraction (HFpEF) is a chronic disease associated with high mortality which affects predominantly elderly (> 65 years) hypertensive women with cardiovascular and non-cardiovascular comorbidities. Unfortunately, molecular mechanisms underlying this disease are poorly understood today. A new, but yet untested paradigm, has recently emerged focusing in the crucial role of endothelial cells (EC) in the etiology of HFpEF. The E3 ubiquitine ligase, PDZRN3, a mediator of the non-canonical Wnt pathway, was reported to enhance vascular permeability. Here, we investigated long-term consequences of EC PDZRN3 signaling activation, on heart failure. Study the functional consequences of a damaged vascular system in HFpEF. We have generated triple transgenic mutant mice with post-natal restrictive and inducible EC expression of Pdzrn3 (iEC-Pdzrn3 mice), as exploratory in vivo tool. HFpEF phenotype was explored in 7 months old mice by echocardiography, histology, hemodynamic parameters, Fluorescence Activated Cell Sorting (FACS) and electronic microscopy. At 7 months, iEC-Pdzrn3 mice displayed hemodynamic parameters of HFpEF with a significant strong elevation of the end-diastolic pressure compared with their littermates. A low-grade of inflammation characterized by macrophages and T-cells infiltration was observed on histological heart sections and confirmed by FACS. Electronic microscopy revealed severe vascular alterations, in particular dilated or disrupted vessels along with an enlargement of the perivascular space. Vascular leakage evidenced by fibrinogen and immunoglobulin G vascular extravasation was also observed on cryosections. iEC-Pdzrn3 develop markers of HFpEF within 7 months of life highlighting a causal relationship between vascular dysfunction and HFpEF pathology. Molecular alterations of endothelium, induced by PDZRN3 signaling, are under current investigation.