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

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.

Deletion of Endothelial TRPV4 Protects Heart From Pressure Overload–Induced Hypertrophy

“…Further, VEGFR2 expression was increased in TRPV4 ECKO hearts after TAC compared with TRPV4 lox/lox hearts, suggesting that increased VEGF/VEFR2 signaling may increase coronary angiogenesis in TRPV4 ECKO mice. Previous studies have shown that a lack of VEGFR signaling promotes pressure overload and angiotensin II-induced cardiac hypertrophy, 25,26 supporting a role for VEGF/VEGFR2 signaling in attenuating cardiac hypertrophy and pathological remodeling in TRPV4 ECKO mice. However, the molecular mechanism by which TRPV4 regulates VEGF/VEGFR2 signaling in the heart is not known.…”

Novel Designed Proteolytically Resistant VEGF-B186R127S Promotes Angiogenesis in Mouse Heart by Recruiting Endothelial Progenitor Cells

“…VEGF-B-VEGFR1 mediated cardiac remodeling is crucial following myocardial infarction ( Devaux et al, 2012 ; Räsänen et al, 2021 ; Tirronen et al, 2021 ). We found that Ad-VEGF-B186R127S and Ad-VEGF-B186 induced angiogenesis in the heart muscle while not hampering cardiac performance.…”

Therapeutic Potential of VEGF-B in Coronary Heart Disease and Heart Failure: Dream or Vision?

“…Instead, Korpela et al reported that the C-terminal fragment of the proteolytically spliced VEGF-B186 induced cardiac arrhythmias [ 45 ]. As VEGF-R1 is known to regulate cardiac performance [ 78 ], it is possible that due to the inability to bind to the VEGF-R1, the C-terminal end of the VEGF-B186 provokes arrhythmias via binding to an unidentified receptor in the heart.…”