We investigated the role of Notch signaling in the vascular microenvironment, with particular attention paid to the vascular consequences of Notch signaling disruption in myeloid cells. We adapted an established in vitro model of angiogenesis to recreate interactions between endothelial sprouts and vascular support cells, including macrophages and vascular pericytes. We found that inflammatory polarization of macrophages increased their ability to foster angiogenesis, and that intact Notch signaling was essential to this phenomenon. We also demonstrated a role for Notch/Jagged1 signaling in the interaction between vascular pericytes and endothelial sprouts, the disruption of which limits the growth and maturation of vessel networks.
We have also investigated the role of myeloid Notch signaling in vivo, using a number of developmental and pathological models of angiogenesis. We found that Notch inhibition leads to decreased myeloid cell recruitment to a broad variety of functionally distinct angiogenic sites. Importantly, we observed that myeloid Notch disruption has vascular consequences in both physiological and pathological angiogenesis. Myeloid Notch- inhibited mice exhibit decreased vascular complexity in the deep retinal plexus during development. Additionally, these mice show significantly increased vascular tuft formation in the setting of oxygen-induced retinopathy, suggestive of a heretofore- undescribed role for myeloid Notch signaling in the pathogenesis of this significant human disease.
This body of work increases our understanding of the role of Notch signaling both in the dynamics of myeloid cells and in their specific contribution to angiogenesis in multiple disparate contexts. It also contributes to our understanding of a number of key models of human disease, and may prove useful in the development of novel therapies to treat those diseases. Further, we are confident that our new experimental methodology will allow continued fruitful reductive study of the complex intercellular interactions within the vascular microenvironment.
| Identifer | oai:union.ndltd.org:columbia.edu/oai:academiccommons.columbia.edu:10.7916/D8PV6JHG |
| Date | January 2015 |
| Creators | Tattersall, Ian William |
| Source Sets | Columbia University |
| Language | English |
| Detected Language | English |
| Type | Theses |
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