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Hemodynamics: From Developmental Mechano-transduction to Vascular Injury and Regeneration

Abstract

Hemodynamic shear force is an important determinant of cardiovascular function and development. While mammalian models combined with next regeneration sequencing are essential for diagnosis and drug discovery, zebrafish has emerged as an important developmental model that combines in vivo analyses of cardiovascular phenotypes and the advantages of forward and reverse genomic engineering. The following studies in this thesis utilize an advanced imaging-based technique to characterize hemodynamic regulation in cardiovascular development and regeneration in embryonic zebrafish. Cardiogenesis involves a series of complex signaling pathways, while imaging cellular dynamics including cardiac trabeculation requires high spatiotemporal resolution. By using four-dimensional light-sheet fluorescent microscopy, we constructed four-dimensional moving domain models of the contracting myocardial wall to investigate hemodynamic regulation of endocardial Notch signaling in facilitating cardiac trabeculation. In vivo modulations of hematopoiesis and atrial contraction or ectopic expressions of Notch Intracellular Cytoplasmic Domain (NICD), suggested distinct flow patterns in myocardial geometry differentially activate endocardial Notch activity for trabecular organization and contractile function. Vascular disorders characterized by ischemic reperfusion injury, such as stroke, myocardial infarction, and peripheral vascular disease, remain the most frequent causes of incapacitating disease and death. Despite numerous efforts, structural and functional vessel recovery remains challenging, while molecular events underlying vascular injury and regeneration are largely unknown. A plethora of epidemiological studies consistently supports a link between redox active ultrafine particles (UFP, diameter < 0.1 um) in primary pollutants and cardiopulmonary disease. Due to the small size and the light weight of the particle, aspiration of UFP allows for penetration of pulmonary systems as well as the endothelial barrier. Once particles enter the circulatory system, they systematically affect endothelial homeostasis by promoting vascular oxidative and inflammatory responses. However, epigenetic and pathological effects underlying vascular regeneration upon particle exposure remains elusive. For the second part of this thesis, we investigated the importance of the Forkhead Box Sub-family O1 (FOXO1)/Notch activation complex upon UFP exposure in vascular regeneration. Finally, our vascular protective metabolomic profiles suggested hemodynamic shear forces is a central player in modulating the expression levels of glycolytic metabolites. In this context, we investigated the Vascular Endothelial Growth Factor Receptor (VEGFR)-Protein Kinase C isoform epsilon (PKCɛ) pathway and its role in promoting pro-glycolytic metabolites to help facilitate vascular regeneration.

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