Up-regulation of soluble vascular endothelial growth factor receptor-1 prevents angiogenesis in hypertrophied myocardium

Kaza, Elisabeth; Ablasser, Klemens; Poutias, Dimitrios; Griffiths, Eric; Saad, Fawzy A.; Hofstaetter, Jochen G.; Nido, Pedro J. del; Friehs, Ingeborg

doi:10.1093/cvr/cvq321

Cited by 28 publications

(29 citation statements)

References 41 publications

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“…Furthermore, mesothelin levels were previously found to be higher in patients with impaired renal function, which is in accordance with our results [29]. Angiogenin and VEGFR1, which had the highest levels in young patients, were linked to angiogenesis and revascularization [30][31][32][33]. Both markers are pathophysiologically involved in vascular repair and cardiac remodeling, both of which are etiological factors for the development of HFrEF.…”

Section: Discussionsupporting

confidence: 92%

Acute heart failure in the young: Clinical characteristics and biomarker profiles

Tromp

Meyer

Mentz

et al. 2016

International Journal of Cardiology

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Section: Discussionsupporting

confidence: 92%

Acute heart failure in the young: Clinical characteristics and biomarker profiles

Tromp

Meyer

Mentz

et al. 2016

International Journal of Cardiology

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“…While the homeostatic role of VEGF-A in the myocardium has been well established 39 and inhibition of VEGF signaling has been shown to trigger myocardial hibernation, 39 upregulation of the expression of soluble growth factor receptor 1 (sVEGFR1 or sFlt-1) has been shown to prevent angiogenesis in the hypertrophied myocardium. 73 We found that the sFlt-1 protein concentration in the serum and RV tissues trended toward being increased in SuHx rats (Figs. 1I, 2G).…”

Section: Discussionmentioning

confidence: 71%

Vascular Endothelial Growth Factor Receptor 3 Signaling Contributes to Angioobliterative Pulmonary Hypertension

et al. 2015

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The mechanisms involved in the development of severe angioobliterative pulmonary arterial hypertension (PAH) are multicellular and complex. Many of the features of human severe PAH, including angioobliteration, lung perivascular inflammation, and right heart failure, are reproduced in the Sugen 5416/ chronic hypoxia (SuHx) rat model. Here we address, at first glance, the confusing and paradoxical aspect of the model, namely, that treatment of rats with the antiangiogenic vascular endothelial growth factor (VEGF) receptor 1 and 2 kinase inhibitor, Sugen 5416, when combined with chronic hypoxia, causes angioproliferative pulmonary vascular disease. We postulated that signaling through the unblocked VEGF receptor VEGFR3 (or flt4) could account for some of the pulmonary arteriolar lumen-occluding cell growth. We also considered that Sugen 5416-induced VEGFR1 and VEGFR2 blockade could alter the expression pattern of VEGF isoform proteins. Indeed, in the lungs of SuHx rats we found increased expression of the ligand proteins VEGF-C and VEGF-D as well as enhanced expression of the VEGFR3 protein. In contrast, in the failing right ventricle of SuHx rats there was a profound decrease in the expression of VEGF-B and VEGF-D in addition to the previously described reduction in VEGF-A expression. MAZ51, an inhibitor of VEGFR3 phosphorylation and VEGFR3 signaling, largely prevented the development of angioobliteration in the SuHx model; however, obliterated vessels did not reopen when animals with established PAH were treated with the VEGFR3 inhibitor. Part of the mechanism of vasoobliteration in the SuHx model occurs via VEGFR3. VEGFR1/VEGFR2 inhibition can be initially antiangiogenic by inducing lung vessel endothelial cell apoptosis; however, it can be subsequently angiogenic via VEGF-C and VEGF-D signaling through VEGFR3.

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“…7,8 In clinical settings, plasma levels of sFlt-1 are not only directly correlated with the severity of heart failure but also strongly associated with poor outcomes in patients with heart failure.…”

Section: Suppressed Production Of Soluble Fms-like Tyrosine Kinase-1 mentioning

confidence: 99%

“…2 Recently, it has been shown that sFlt-1 is implicated in the pathogenesis of cardiovascular disease. [3][4][5][6][7][8][9][10] In a series of previous studies, 3,4,11 we demonstrated that sFlt-1 production is decreased in patients with chronic kidney disease (CKD) and in an experimental model of renal failure 3 and that decreased sFlt-1 production correlates with the development of atherosclerosis and cardiovascular events. 3,4 Furthermore, previous reports showed that the gene delivery of sFlt-1 suppresses atherosclerosis development in an animal model, 5 and the increase in sFlt-1 levels induced by atorvastatin treatment is associated with improvement of ventricular Seno et al sFlt-1 and Heart Failure 679 function in patients with acute coronary syndrome.…”

mentioning

confidence: 93%

Suppressed Production of Soluble Fms-Like Tyrosine Kinase-1 Contributes to Myocardial Remodeling and Heart Failure

et al. 2016

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Abstract-Soluble fms-like tyrosine kinase-1 (sFlt-1), an endogenous inhibitor of vascular endothelial growth factor and placental growth factor, is involved in the pathogenesis of cardiovascular disease. However, the significance of sFlt-1 in heart failure has not been fully elucidated. We found that sFlt-1 is decreased in renal failure and serves as a key molecule in atherosclerosis. In this study, we aimed to investigate the role of the decreased sFlt-1 production in heart failure, using sFlt-1 knockout mice. sFlt-1 knockout mice and wild-type mice were subjected to transverse aortic constriction and evaluated after 7 days. The sFlt-1 knockout mice had significantly higher mortality (52% versus 15%; P=0.0002) attributable to heart failure and showed greater cardiac hypertrophy (heart weight to body weight ratio, 8.95±0.45 mg/g in sFlt-1 knockout mice versus 6.60±0.32 mg/g in wild-type mice; P<0.0001) and cardiac dysfunction, which was accompanied by a significant increase in macrophage infiltration and cardiac fibrosis, than wild-type mice after transverse aortic constriction. An anti-placental growth factor-neutralizing antibody prevented pressure overload-induced cardiac hypertrophy, fibrosis, and cardiac dysfunction. Moreover, monocyte chemoattractant protein-1 expression was significantly increased in the hypertrophied hearts of sFlt-1 knockout mice compared with wild-type mice. Monocyte chemoattractant protein-1 inhibition with neutralizing antibody ameliorated maladaptive cardiac remodeling in sFlt-1 knockout mice after transverse aortic constriction. In conclusion, decreased sFlt-1 production plays a key role in the aggravation of cardiac hypertrophy and heart failure through upregulation of monocyte chemoattractant protein-1 expression in pressure-overloaded heart. Correspondence to Yoshihiko Saito, First Department of Internal Medicine, Nara Medical University, 840 Shijo-cho, Kashihara, Nara, 634-8522, Japan. E-mail saitonaramed@gmail.com Suppressed Production of Soluble Fms-Like Tyrosine Kinase-1 Contributes to MyocardialRemodeling and Heart Failure Ayako Seno, Yukiji Takeda, Masaru Matsui, Aya Okuda, Tomoya Nakano, Yasuki Nakada, Takuya Kumazawa, Hitoshi Nakagawa, Taku Nishida, Kenji Onoue, Satoshi Somekawa, Makoto Watanabe, Hiroyuki Kawata, Rika Kawakami, Hiroyuki Okura, Shiro Uemura, Yoshihiko Saito © 2016 American Heart Association, Inc. function in patients with acute coronary syndrome. 6 Therefore, it seems that insufficient sFlt-1 production is associated with adverse cardiovascular outcomes.On the contrary, several previous reports have shown that upregulation of sFlt-1 contributes to the development of heart failure, with antiangiogenesis activity by binding to VEGF. 7,8 In clinical settings, plasma levels of sFlt-1 are not only directly correlated with the severity of heart failure but also strongly associated with poor outcomes in patients with heart failure.9,10 These observations provide a plausible interpretation that increased sFlt-1 production aggravates heart failure with adverse car...

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Up-regulation of soluble vascular endothelial growth factor receptor-1 prevents angiogenesis in hypertrophied myocardium

Cited by 28 publications

References 41 publications

Acute heart failure in the young: Clinical characteristics and biomarker profiles

Acute heart failure in the young: Clinical characteristics and biomarker profiles

Vascular Endothelial Growth Factor Receptor 3 Signaling Contributes to Angioobliterative Pulmonary Hypertension

Suppressed Production of Soluble Fms-Like Tyrosine Kinase-1 Contributes to Myocardial Remodeling and Heart Failure

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