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Light-Sheet Fluorescence Microscopy and Molecular Imaging to Elucidate Mechanisms of Cardiovascular Development and Disease

  • Author(s): Hsu, Jeffrey John
  • Advisor(s): Demer, Linda L
  • et al.

Cardiovascular development is a highly complex, coordinated process, and the investigation of the mechanisms governing this process has led to the identification of genes that not only orchestrate cardiovascular development, but also modulate disease processes in adulthood. The Notch signaling pathway, for instance, has been shown to orchestrate cardiac valve development during embryogenesis, while also regulating pathological aortic valve calcification in adulthood. Therefore, a deeper understanding of the mechanisms of cardiovascular development can help inform our research into pathophysiological processes such as ectopic calcification. The studies in this dissertation utilize advanced imaging techniques to examine the mechanobiological mechanisms of cardiac valve development and disease.

In the first study, four-dimensional light-sheet fluorescence microscopy imaging of embryonic zebrafish hearts was combined with moving-domain computational fluid dynamic modeling to evaluate the relative influences of contractile and hemodynamic shear forces on cardiac valve development. The results showed that contractile forces appear to be necessary for initial cardiac valve formation, whereas hemodynamic shear forces contribute to valve leaflet growth. Further, these processes appear to occur by mechanosensitive, Notch1b-mediated endothelial-to-mesenchymal transition.

In the second study, fused 18F-NaF micro-positron emission tomography / micro-computed tomography (uPET/uCT) imaging was performed on aged hyperlipidemic mice to evaluate the effects of an osteoporosis therapeutic drug, teriparatide, on the morphology of aortic calcification. The evidence presented shows that while teriparatide, a parathyroid hormone analog, does not affect the progression of pre-existing aortic calcification, it promotes the coalescence of calcification into macro-calcium deposits. These studies suggest that teriparatide therapy may promote a macrocalcification phenotype in atherosclerotic calcification, with potential implications on plaque stability.

In summary, these studies demonstrate the use of advanced imaging modalities, such as light-sheet microscopy and 18F-NaF-uPET/uCT imaging, to investigate the mechanobiological mechanisms of cardiovascular development, as well as cardiovascular disease, such as calcification.

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