Metabolic and cellular signaling during cardiovascular homeostasis
Alterations in cell metabolism can quickly change the redox state of cells by perturbing the balance between antioxidant and reactive oxygen species (ROS). The mechanisms through which metabolic pathways control cellular redox state and antioxidant response are still unknown. A clear understanding of these events are particularly important for vascular tissues since these cells are more often exposed to oxidative stress conditions (e.g. hyperglycemia, mechanical stress). Our goal is to expand the current knowledge of the metabolic pathways regulating vascular redox homeostasis in living organisms. To accomplish this function we take advantage of vertebrate models including zebrafish. The zebrafish model system has proven to be a powerful vertebrate model system for the genetic analysis of developmental pathways and is only beginning to be exploited as a model for human disease and clinical research.
Our lab is focused on three specific projects:
1) Metabolic-Redox signaling in normal and tumor angiogenesis
2) Cardiovascular development and homeostasis using the zebrafish vertebrate system
3) Apoptotic pathways in endothelial cells
The development, function and remodeling of the vasculature is closely linked to the metabolic needs of the tissues it serves - whether that tissue is an essential organ or a pathological abnormality such as a tumor. Such metabolic requirements influence the redox state of cells providing an unique system where to identify the molecular mechanism required to regulate redox signaling in these cells. Tools to investigate the complexity of molecular, cellular, and metabolic interactions amongst different tissues in vivo have only recently become available. We are currently investigating how lipid signaling, endothelial dynamics, and metabolic regulation converge during normal development and homeostasis. Such studies will offer unique prospects for designing new therapeutic strategies (Mugoni et al., 2012 Cell in
Zebrafish system represents an optimal model for cardiovascular studies. Zebrafish embryos are not completely dependent on a functional cardiovascular system to continue to survive and develop, because embryos receive enough oxygen by passive diffusion, thereby allowing a detailed analysis of animals with severe vascular defects. Further, the striking transparency of the embryos facilitates morphological observation of internal organs in vivo under a simple stereomicroscope, also at the single-cell level. The cardiovascular system is the first organ to form and function during embryonic development. Its correct development is essential for the proper formation of vertebrate embryos as well as for adulthood. Using a set of new cellular, molecular, and genetic approaches (e.g. ZNF nuclease, Cre-Lox, ENU screening, BAC recombineering) as well as advanced microscopic techniques (e.g. multi-photon microscopy and SPIM), we propose to elucidate how endothelial and mural cells cooperate to shape the cardiovascular system and regulate vascular maturation and myogenesis. The long-term goal is to provide additional molecular entry points to further investigate EC maturation and MC differentiation in normal and pathological conditions. In particular, we will focus on the role of microRNA in cardiovascular development and homeostasis (Fish et al., 2008; Santoro, 2011, Gays and Santoro, 2012).
In this project we will address the role of IAP-tosome in endothelial cell survival and apoptosis. In the past we characterized a zebrafish null mutant of IAP1 (BIRC2), called tomato (Santoro et al., 2007), characterized by specific endothelial cell survival defects. We are currently investigating the role of new components of IAP-tosome signaling platform that are involved in vascular cell survival. Identification and characterization of such new anti-apoptotic molecular players can become selective target for anti-tumor angiogenesis drug screening (Santoro et al., 2007; Danio and Santoro, 2012 in preparation). Cross-talk signaling between NADPH-dependent oxido-reductase and TNF receptor signaling platform in endothelial cells is also under investigation.
The Marie Curie Action program "ANGIOFISH" is supporting this research.