Abstract 2523: Endogenous Angiogenesis Inhibitors Prevent Adaptive Capillary Growth in Hypertrophying Myocardium
Objective: In pressure-overload hypertrophy, lack of adaptive capillary growth impairs myocardial perfusion and substrate delivery contributing to progression to failure. A variety of factors influence the process of myocardial vascularization, including the balance of pro-angiogenic growth factors such as vascular endothelial growth factor (VEGF) and angiogenesis inhibitors. Angiogenesis is an invasive process that requires proteolysis of extracellular matrix, carried out by matrix metalloproteinases (MMPs) with MMP-9 being one representative. At the same time, MMP-9 can process plasminogen to generate the angiogenesis inhibitor angiosta-tin. We sought to determine whether angiostatin levles are elevated in hypertrophying myocardium at the onset of failure and whether its release is regulated by MMP-9 leading to lack of adaptive capillary growth.
Methods: Newborn rabbits underwent aortic banding. At 7wks, LV tissue from banded (n=5–7) and age-matched animals (n=3–6) was analyzed by immunohistochemistry with FITC-labeled lectin for capillary density, and immunoblotting (expressed as arbitrary densitometry units) for VEGF, angiostatin and MMP-9 on immunopre-cipitated samples identifying the inactive and active forms. Data are expressed as mean±SEM. P<0.05 by two-tailed t-test was considered significant.
Results: see Table⇓; *p<0.05 versus Control
Conclusions: These results indicate that lack of angiogenesis in the hypertrophying myocardium in response to pressure overload is not a result of reduced production of pro-angiogenic growth factors (VEGF). Instead, enhanced levels of angiogenesis inhibitors (angiostatin) play a critical role in this process. Future therapeutic approaches to prevent heart failure in pressure-overload hypertrophy should focus not only on enhancing pro-angiogenic proteins but also on suppressing angiogenesis inhibitors.