Interindividual heterogeneity in the hypoxic regulation of VEGF - Significance for the development of the coronary artery collateral circulation

Background-The coronary artery collateral circulation may be beneficial in protecting against myocardial ischemia and necrosis. However, there is a tr emendous interindividual variability in the degree of new collateral format ion in patients with coronary artery disease. The basis for this interindiv idual heterogeneity is not understood. In this study we test the hypothesis that failure to generate collateral vessels is associated with a failure t o appropriately induce with hypoxia or ischemia the angiogenic factor, vasc ular endothelial growth factor (VEGF). Methods and Results-We correlated the VEGF response to hypoxia in the monoc ytes harvested from patients with coronary artery disease with the presence of collaterals visualized during routine angiography. We found that there was a highly significant difference in the hypoxic induction of VEGF in pat ients with no collaterals compared with patients with some collaterals (mea n fold induction 1.9+/-0.2 versus 3.2+/-0.3, P < 0.0001). After subjecting the data to ANCOVA, using as covariates a number of factors that might infl uence the amount of collateral formation (ie, age, sex, diabetes, smoking, hypercholesterolemia), patients with no collaterals still have a significan tly lower hypoxic induction of VEGF than patients with collaterals. Conclusions-This study provides evidence in support of the hypothesis that the ability to respond to progressive coronary artery stenosis is strongly associated with the ability to induce VEGF in response to hypoxia. The obse rved interindividual heterogeneity in this response may be due to environme ntal, epigenetic, or genetic causes. This interindividual heterogeneity may also help to explain the variable angiogenic responses seen in other condi tions such as diabetic retinopathy and solid tumors.