The Ablation of VEGFR-1 Signaling Promotes Pressure Overload-Induced Cardiac Dysfunction and Sudden Death.

Annakaisa Tirronen,Nicholas L Downes,Marja Hedman,Seppo Ylä-Herttuala,Pasi Tavi,Johanna P Laakkonen,Tomi Tuomainen,Jenni Huusko

doi:10.3390/biom11030452

Abstract

Molecular mechanisms involved in cardiac remodelling are not fully understood. To study the role of vascular endothelial growth factor receptor 1 (VEGFR-1) signaling in left ventricular hypertrophy (LVH) and heart failure, we used a mouse model lacking the intracellular VEGFR-1 tyrosine kinase domain (VEGFR-1 TK−/−) and induced pressure overload with angiotensin II infusion. Using echocardiography (ECG) and immunohistochemistry, we evaluated pathological changes in the heart during pressure overload and measured the corresponding alterations in expression level and phosphorylation of interesting targets by deep RNA sequencing and Western blot, respectively. By day 6 of pressure overload, control mice developed significant LVH whereas VEGFR-1 TK−/− mice displayed a complete absence of LVH, which correlated with significantly increased mortality. At a later time point, the cardiac dysfunction led to increased ANP and BNP levels, atrial dilatation and prolongation of the QRSp duration as well as increased cardiomyocyte area. Immunohistochemical analyses showed no alterations in fibrosis or angiogenesis in VEGFR-1 TK−/− mice. Mechanistically, the ablation of VEGFR-1 signaling led to significantly upregulated mTOR and downregulated PKCα phosphorylation in the myocardium. Our results show that VEGFR-1 signaling regulates the early cardiac remodelling during the compensatory phase of pressure overload and increases the risk of sudden death.

Highlights

We studied what molecular changes the deficiency of VEGFR1 signaling induces in the myocardium and whether it has a role in cardiac angiogenesis
Several publications have shown that vascular endothelial growth factor receptor 1 (VEGFR-1) ligands VEGF-A and VEGF-B in the heart induce left ventricular hypertrophy (LVH) and angiogenesis as well as regulate cardiac function [7,8,19]
To test whether VEGFR-1 signaling is involved in these processes, we studied cardiac function at baseline and during pressure overload using domain–specific knockout mouse lacking the intracellular VEGFR-1 tyrosine kinase domain (TK−/− )

Summary

Introduction

The continuous prolongation of the mean life expectancy and the increase in additional risk factors such as obesity, coronary artery disease and hypertension are the main attributes to the high incidence. Patients with heart failure commonly have a history of hypertension and consequent left ventricular hypertrophy (LVH) [3]. When pressure overload is sustained, cardiac remodelling occurs, as an adaptive response, which includes development of LVH combined with diastolic and/or systolic dysfunction. This leads to decompensated hypertrophy characterised by contractile dysfunction, reduced coronary flow reserve, interstitial fibrosis, as well as changes in metabolism and electrophysiology, triggering clinically evident heart failure

Methods

Results

Conclusion