The Ablation of VEGFR-1 Signaling Promotes Pressure Overload-Induced Cardiac Dysfunction and Sudden Death
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 domai...
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doaj-93b4a1806b00496a9c09ef69d95852692021-03-18T00:05:56ZengMDPI AGBiomolecules2218-273X2021-03-011145245210.3390/biom11030452The Ablation of VEGFR-1 Signaling Promotes Pressure Overload-Induced Cardiac Dysfunction and Sudden DeathAnnakaisa Tirronen0Nicholas L. Downes1Jenni Huusko2Johanna P. Laakkonen3Tomi Tuomainen4Pasi Tavi5Marja Hedman6Seppo Ylä-Herttuala7A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, 70211 Kuopio, FinlandA.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, 70211 Kuopio, FinlandA.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, 70211 Kuopio, FinlandA.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, 70211 Kuopio, FinlandA.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, 70211 Kuopio, FinlandA.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, 70211 Kuopio, FinlandInstitute of Clinical Medicine, University of Eastern Finland, 70029 Kuopio, FinlandA.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, 70211 Kuopio, FinlandMolecular 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<sup>−/−</sup>) 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<sup>−/− </sup>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<sup>−/− </sup>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.https://www.mdpi.com/2218-273X/11/3/452VEGFR-1Flt1heart failureHFpEFhypertrophypressure overload |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Annakaisa Tirronen Nicholas L. Downes Jenni Huusko Johanna P. Laakkonen Tomi Tuomainen Pasi Tavi Marja Hedman Seppo Ylä-Herttuala |
spellingShingle |
Annakaisa Tirronen Nicholas L. Downes Jenni Huusko Johanna P. Laakkonen Tomi Tuomainen Pasi Tavi Marja Hedman Seppo Ylä-Herttuala The Ablation of VEGFR-1 Signaling Promotes Pressure Overload-Induced Cardiac Dysfunction and Sudden Death Biomolecules VEGFR-1 Flt1 heart failure HFpEF hypertrophy pressure overload |
author_facet |
Annakaisa Tirronen Nicholas L. Downes Jenni Huusko Johanna P. Laakkonen Tomi Tuomainen Pasi Tavi Marja Hedman Seppo Ylä-Herttuala |
author_sort |
Annakaisa Tirronen |
title |
The Ablation of VEGFR-1 Signaling Promotes Pressure Overload-Induced Cardiac Dysfunction and Sudden Death |
title_short |
The Ablation of VEGFR-1 Signaling Promotes Pressure Overload-Induced Cardiac Dysfunction and Sudden Death |
title_full |
The Ablation of VEGFR-1 Signaling Promotes Pressure Overload-Induced Cardiac Dysfunction and Sudden Death |
title_fullStr |
The Ablation of VEGFR-1 Signaling Promotes Pressure Overload-Induced Cardiac Dysfunction and Sudden Death |
title_full_unstemmed |
The Ablation of VEGFR-1 Signaling Promotes Pressure Overload-Induced Cardiac Dysfunction and Sudden Death |
title_sort |
ablation of vegfr-1 signaling promotes pressure overload-induced cardiac dysfunction and sudden death |
publisher |
MDPI AG |
series |
Biomolecules |
issn |
2218-273X |
publishDate |
2021-03-01 |
description |
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<sup>−/−</sup>) 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<sup>−/− </sup>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<sup>−/− </sup>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. |
topic |
VEGFR-1 Flt1 heart failure HFpEF hypertrophy pressure overload |
url |
https://www.mdpi.com/2218-273X/11/3/452 |
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