Abstract 3273: Inhibition of Soluble VEGFreceptor-1 With Placental Growth Factor Induces Capillary Growth in Hypertrophied Myocardium
Objective: Capillary growth is tightly linked to contractile function in pressure-overload hypertrophy. We have previously shown that capillary growth is restricted due to an imbalance of 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). We sought to determine whether blocking of sVEGFR-1 with Placental Growth Factor (PlGF), a specific ligand for VEGFR-1/sVEGFR-1, induces angiogenesis by balancing VEGF release and sVEGFR-1 production.
Methods: Neonatal rabbits underwent aortic banding. At 4wks (peak hypertrophy) and 6wks (early failure), rhPlGF (2μg/kg) was administered intrapericardially to hypertrophied animals. Progression of hypertrophy (mass/volume ratio) and contractile function (shorting fraction) were determined by echocardiography. Capillary density (immunohistochemistry), VEGF release from sVEGFR-1 (ELISA), mRNA levels of VEGF, VEGFR-2, VEGFR-1, sVEGFR-1 (qRT-PCR) were measured in controls (C), hypertrophied (H), and hypertrophied+PlGF hearts (H+PlGF). Data (6–8/group) are expressed as mean±SEM with ANOVA for testing (p≤0.05).
Results: At 7wks, contractile function was preserved in H+PlGF versus H comparable to controls (H+PlGF:40±2 and C:45±1 vs H:17±1; p<0.001) accompanied by continuous adaptive hypertrophic growth of the LV in H+PlGF hearts (H+PlGF:2.4±0.2 and C:1.1±0.1 vs H:0.6±0.04; p<0.001). Inhibition of sVEGFR-1 by PlGF resulted in a significant increase in free, unbound VEGF protein (H+PlGF: 7.4±0.5 and C:7.2±0.4 vs H:5.2±0.2pg/ml; p<0.001) and endogenous production of VEGF (mRNA expression ratio with 10-fold increase vs C and 7-fold increase vs H). At the same time, PlGF administration inhibited production and release of sVEGFR-1 (mRNA expression ratio with 3-fold down-regulation vs H and C) which resulted in capillary growth in hypertrophied hearts exposed to PlGF (H+PlGF: 1.9±0.1 and C:1±0.01 vs H:0.7±0.02capillaries/nuclei; p<0.001).
Conclusion: Inhibition of sVEGFR-1 by PlGF releases VEGF protein to stimulate endogenous production of VEGF and down-regulates sVEGFR-1 release, tipping the balance of pro- versus anti-angiogenic stimuli in a favorable direction.