Metabolic disorders affect tissue renewal potential leading to organ dysfunction. Diabetic patients develop heart failure after ischemia at more than double the rate of non-diabetics. This suggests a defective repair system resulting in adverse cardiac remodeling. Tissue architecture homeostasis involves the coordinated interaction of multiple cell types. Aberrant environmental cues and changes in cell signaling networks are central to the development of a defective repair process. This project is designed to investigate the key cellular and molecular mechanisms affecting tissue repair in diabetes, combining genetic disease mouse models and in vitro studies. We will study diabetic cardiovascular disease as the result of defective repair processes, focusing on microcirculation. In paticular we will address the key role of PDE5-cGMP axis in cardiac vascular compartment. The project will use unique genetic mouse model to address the PDE5 restoring angiogenic capacity. To investigate how endothelial cell integrity controls trafficking immuno-cells involved in angiogenesis and guides the pericytes reorganizing microvascular architecture. We will explore if pharmacological and genetic modulation of PDE5 regulates proangiogenic monocytes and it will be explored at cellular, molecular and ultrastructural level, cardiac response to injury.
