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.
Unfavorable metabolic conditions impair normal tissue homeostasis, leading to pathologic remodeling and dysfunction. Studying NO/cGMP deficiency effects, common downstream pathways of Tie2, VEGF, endothelial and circulating angiogenic cells, tissue-specific and mesenchymal stem cells in metabolic disorders could lead to the development of promising specific therapeutic targets for cardiovascular protection. Local Ang1, Ang2 imbalances could be controlled using specific modulators of their expression. The crucial role of TEMs in the pathogenesis of vascular repair and tissue remodeling in metabolic diseases could be a novel marker to monitor and improve vascular complications in diabetes. The study immuno-cells, largely neglected in diabetic mellitus, may offer a new paradigm of diabetic tissue damage.
This project could identify new molecular pathways involving the re-education of hematopoietic cells to treat diabetic vascular disease.
We generated a unique PDE5-/- null or conditional ko mouse model with endothelial (Tie2) selectivity that can be used to investigate i) the differential contribution of altered microcirculation vs. altered cardiomyocyte cGMP in the features of diabetic cardiomyopathy selectivity and to study ii) the contribution of cGMP/PDE5 axis in the instauration of endothelial disfunction.
Elucidating which vascular repair mechanisms are altered in mouse tissues observed in metabolic conditions such as diabetes and obesity and the role played by PDE5 in vascular repair will clarify the role of this key enzyme as a potential regulator of vascular impairment in cardiac tissue, thus enabling the development of selective therapies to modulate diabetic vascular disease.
Emerging evidence shows that angiogenesis modulators affect the expansion and metabolism of tissue vasculature. Tie2, tyrosine kinase receptor, modulation may control vessel structure and architecture. Understanding the mechanisms by which angiogenesis and vasculature modulate immune-cells functions may provide new therapeutic options for treating obesity and metabolic disorders. Restoring the disrupted balance of macrophage populations and angiogenesis could improve lipid and glucose metabolism and improve insulin sensitivity.
In this scenario, TEMs could also serve as a new, robust and accessible marker to monitor vascular complication in diabetes.