Up-regulation of soluble vascular endothelial growth factor receptor-1 prevents angiogenesis in hypertrophied myocardium
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...
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Veröffentlicht in: | Cardiovascular research 2011-02, Vol.89 (2), p.410-418 |
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Zusammenfassung: | 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.
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.
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. |
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ISSN: | 0008-6363 1755-3245 |
DOI: | 10.1093/cvr/cvq321 |