Medizinische Universität Graz - Research portal
Selected Publication:
Scherr, E.
REGULATION OF ANGIOGENESIS IN PRESSURE-OVERLOAD HYPERTROPHY
[ Dissertation ] Medical University of Graz; 2009. pp. 120
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- Authors Med Uni Graz:
- Advisor:
- Gasser Robert
- Zweiker Robert
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- Abstract:
- Inadequate capillary growth in pressure-overload left ventricular hypertrophy impairs myocardial perfusion and substrate delivery, contributing to progression and heart failure. New capillary development is tightly regulated by pro-angiogenic growth factors such as Vascular Endothelial Growth Factor (VEGF) and endogenous angiogenesis inhibitors such as the splice variant of VEGFReceptor-1 (sVEGFR-1). Binding of VEGF to sVEGFR-1 restricts the amount of VEGF available for VEGFR-2 activation to induce angiogenesis. We hypothesized that in pressure-overload hypertrophy, inadequate VEGF isoform expression and differential expression zof VEGF receptors determine capillary growth in LV hypertrophy at the onset of failure. Banding of the thoracic aorta was performed in 10-day-old NZW rabbits. Tissue was harvested for RNA and protein isolation at 6wks of age (early decompensation) in hypertrophied and control animals (6-12/group). mRNA expression of total VEGF, VEGF isoforms (121,165, 189), VEGFR-1, sVEGFR-1 and VEGFR-2 was performed by SYBR green qRT-PCR and normalized to GAPDH and 18S. Protein levels were determined by immunoblotting and expressed as arbitrary densitometry units. Immunoprecipitation was performed to demonstrate binding of VEGF to sVEGFR-1. Data are expressed as meanSEM with p<0.05 considered significant by t-test. mRNA and protein levels of VEGFR-1 and sVEGFR-1 were significantly up-regulated in hypertrophied hearts (mRNA expression ratio - 7 fold up-regulated; protein levels - VEGFR-1: Hypertrophy: 448 vs. Control: 231; p=0.031 and sVEGFR-1: Hypertrophy: 7113 vs. Control: 313; p=0.016.) There was no difference in total VEGF (Control: 1844 vs. Hypertrophy: 1734; p=0.063) or any of the isoform mRNA or protein levels nor with VEGFR-2 (Control: 182 versus Hypertrophy: 204; p=0.662). Co-immunoprecipitation with sVEGFR-1 confirmed binding to VEGF in vivo. These results indicate that lack of angiogenic response in pressure-overload, which leads to heart failure, is likely due to up-regulation of VEGFR-1 and its splice variant, the soluble VEGFR-1. Strategies aimed at up-regulating VEGF or binding the soluble VEGFR-1 may be useful in maintaining capillary density and preventing heart failure.