VEGFB is highly expressed in metabolically active tissues, such as the heart and skeletal muscle, suggesting a function in maintaining oxidative metabolic and contractile function in these tissues. Multiple models of heart failure have indicated a significant drop in VEGFB. However, whether there is a role for decreased VEGFB in diabetic cardiomyopathy is currently unknown. Of the VEGFB located in cardiomyocytes, there is a substantial and readily releasable pool localized on the cell surface. The immediate response to high glucose and the secretion of endothelial heparanase is the release of this surface bound VEGFB, which triggers signaling pathways and gene expression to influence endothelial cell (autocrine action) and cardiomyocyte (paracrine effects) survival. Under conditions of hyperglycemia, when VEGFB production is impaired, a robust increase in VEGFR1 expression ensues as a possible mechanism to enhance or maintain VEGFB signaling. However, even with an increase in VEGFR1 following diabetes, cardiomyocytes are unable to respond to VEGFB. In addition to the loss of VEGFB production and signaling, evaluation of latent heparanase, the protein responsible for VEGFB release, also showed a significant decline in expression in whole hearts from animals with chronic or acute diabetes. Defects in these numerous VEGFB pathways were associated with an increased cell death signature in our models of diabetes. Through this bi-directional interaction between ECs (which secrete heparanase) and cardiomyocytes (which release VEGFB), this growth factor could provide the diabetic heart protection against cell death, and may be a critical tool to delay or prevent cardiomyopathy.
- Cell death
- Copyright © 2016, American Journal of Physiology-Heart and Circulatory Physiology