Effect of chronic vascular stresses on angiogenic signaling.

摘要

A common element of many disease states like cancer, diabetes mellitus (DM) and cardiovascular disease (CVD) is chronic vascular stress that profoundly alters the micro- and macro-vasculature by mediating pathological changes in angiogenic and stress signaling pathways. The foundation of our studies was three major chronic vascular stresses: namely hypoxia in terms of tumor progression, environmental levels of arsenic (III) in terms of tumorigenesis, and a combination of high glucose with mild hypoxia with respect to diabetic complications. The first unique finding common to all three stresses was that chronic, sustained stresses behave very differently than acute, short-term stresses. More specifically, we found that chronic hypoxia differentially regulates the expression and activity of hypoxia inducible factor (HIF-1alpha), a key mediator of hypoxia as well as non-hypoxic stimuli, in a dose dependent manner as compared to acute hypoxic exposures in tumor cells. We also discovered that p53 status was crucial for deciding the cellular phenotype of the cells under chronic hypoxia. It was next found that only chronic (and not acute) exposure to low dose As(III) was capable of stimulating HIF signaling and VEGF expression in tumors in vivo as well as in isolated tumor, smooth muscle and endothelial cells. In the final set of experiments, it was found that hyperglycemia alone downregulates HIF-1alpha and HIF-2alpha while hyperglycemia together with hypoxia to mimic diabetics with CVD upregulates both HIF-1alpha, HIF-2alpha, and VEGF protein levels, suggesting an underlying increase in angiogenic signaling. In addition, the presence of a cellular "persistence" for the exposure to hypoxia persists even after normalization of the oxygen conditions and appears to be ROS-mediated. Taken together, our findings strongly suggest that target cells respond very differently to chronic as compared to acute vascular stresses and suggest the need for more aggressive, and efficient anti-angiogenic therapy for tumor control and antioxidant therapy together with glucose and oxygen normalization for DM and CVD.