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

被引：30

作者：

Kaza, Elisabeth ^{[1
]}

Ablasser, Klemens ^{[1
]}

Poutias, Dimitrios ^{[1
]}

Griffiths, Eric R. ^{[1
]}

Saad, Fawzy A. ^{[2
]}

Hofstaetter, Jochen G. ^{[2
]}

del Nido, Pedro J. ^{[1
]}

Friehs, Ingeborg ^{[1
]}

机构：

[1] Harvard Univ, Sch Med, Childrens Hosp Boston, Dept Cardiac Surg, Boston, MA 02115 USA

[2] Harvard Univ, Sch Med, Childrens Hosp Boston, Dept Orthoped Surg, Boston, MA 02115 USA

来源：

CARDIOVASCULAR RESEARCH | 2011年 / 89卷 / 02期

关键词：

Angiogenesis; Hypertrophy; Angiogenesis inhibitor; Placental growth factor; PRESSURE-OVERLOAD HYPERTROPHY; HIGH-AFFINITY BINDING; TYROSINE KINASE; VEGF; FLT-1; HYPERTENSION; CAPILLARIES; CONTRIBUTES; MORPHOMETRY; ACTIVATION;

D O I：

10.1093/cvr/cvq321

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

Aims Inadequate capillary growth in pressure-overload hypertrophy impairs myocardial perfusion and substrate delivery, contributing to progression to failure. Capillary growth is tightly regulated by angiogenesis growth factors like vascular endothelial growth factor (VEGF) and endogenous inhibitors such as the splice variant of VEGF receptor-1, sVEGFR-1. We hypothesized that inadequate expression of VEGF and up-regulation of VEGFR-1 and its soluble splice variant, sVEGFR-1, restrict capillary growth in pressure-overload hypertrophy. Methods and results Neonatal New Zealand White rabbits underwent aortic banding. mRNA (qRT-PCR) and protein levels (immunoblotting) were determined in hypertrophied and control myocardium (7/group) for total VEGF, VEGFR-1, sVEGFR-1, VEGFR-2, and phospho-VEGFR-1 and -R-2. Free VEGF was determined by enzyme-linked immunoassay (ELISA) in hypertrophied myocardium, controls, and hypertrophied hearts following inhibition of sVEGFR-1 with placental growth factor (PlGF). VEGFR-1 and sVEGFR-1 mRNA (seven-fold up-regulation, P 0.001) and protein levels were significantly up-regulated in hypertrophied hearts vs. controls (VEGFR-1: 44 +/- 8 vs. 23 +/- 1, P = 0.031; sVEGFR-1: 71 +/- 13 vs. 31 +/- 3, P = 0.016). There was no change in VEGF and VEGFR-2 mRNA or protein levels in hypertrophied compared with controls hearts. A significant decline in free, unbound VEGF was found in hypertrophied myocardium which was reversed following inhibition of sVEGFR-1 with PlGF, which was accompanied by phosphorylation of VEGFR-1 and VEGFR-2. Conclusion Up-regulation of the soluble VEGFR-1 in pressure-loaded myocardium prevents capillary growth by trapping VEGF. Inhibition of sVEGFR-1 released sufficient VEGF to induce angiogenesis and preserved contractile function. These data suggest sVEGFR-1 as possible therapeutic targets to prevent heart failure.

引用

页码：410 / 418

页数：9

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