Document Type
Dissertation - Open Access
Award Date
2024
Degree Name
Doctor of Philosophy (PhD)
Department / School
Chemistry and Biochemistry
First Advisor
Darci Fink
Abstract
Lymphatic vasculature develops early in embryogenesis and is classically known for its role in maintaining fluid homeostasis. In addition, the lymphatic plexus infiltrates most tissues and carries out organ specific functions including toxin removal in the heart, lipid absorption in the small intestine and immune cell education and activation within lymph nodes. Lymphangiogenesis (the growth of new lymphatic vessels) aids in acute inflammation resolution by clearing the tissue of cellular debris and immune cells. However, in chronic inflammatory conditions the lymphatic system acts as a conduit for disease progression such as in cancer metastasis. Stimulating and inhibiting lymphangiogenesis is utilized to treat inflammation associated conditions. Dynamic remodeling of endothelial cell-cell junctions gives the lymphatic plexus plasticity and is essential for lymphangiogenesis. VE-cadherin is a major component of interendothelial junctions. Lymphatic capillaries have discontinuous VE-cadherin localization forming button like cell-cell junctions that allow fluid uptake, while larger collecting lymphatics have continuous zipper like junctions that prevent leakage. VEcadherin internalization and thereby functional inhibition is induced via Src mediated phosphorylation following VEGF-R3 activation on lymphatic endothelial cells. VEGF-R3 binding its ligand VEGF-C is the primary pathway governing lymphatic endothelial cell proliferation and migration during lymphatic development and remodeling. While VEGF-R3/C signaling is identified as the canonical driver of lymphatic vessel development and remodeling, gaps remain in our knowledge. Until now, primary ciliary and intraflagellar transport mechanisms regulating lymphatic vessel development and remodeling have gone unstudied. IFT20 is one of many proteins that make up intraflagellar transport machinery and is required for primary cilia assembly. Loss of IFT20 impairs primary cilia assembly on LECs and results in severe lymphatic vessel patterning defects during development and exacerbates inflammation-induced corneal lymphangiogenesis in adult mice. Mature pre-collecting and collecting lymphatic vessels in the cornea and ear dermis of IFT20 KO mice have discontinuous VE-cadherin localization on LECs in contrast to continuous zipper junctions observed in control animals. In addition to its critical role in lymphatic endothelial primary ciliary signaling, we also demonstrate that IFT20 regulates VE-cadherin trafficking post VEGF-C induced internalization. IFT20 KD HDLECs have disrupted VE-cadherin localization and accumulate VE-cadherin in Rab5+ endosomes following VEGF-C stimulation, suggesting IFT20 facilitates VE-cadherin vesicular trafficking following internalization. Together these data suggest primary cilia and intraflagellar transport are essential modulators for lymphatic vessel development and endothelial junction remodeling, providing a new foundation to build on in the field of lymphatic biology.
Publisher
South Dakota State University
Recommended Citation
Paulson, Delayna, "Primary Cilia and Intraflagellar Transport are Essential Regulators of Lymphangiogenesis and Modulate Cellular Trafficking of Ve-Cadherin" (2024). Electronic Theses and Dissertations. 953.
https://openprairie.sdstate.edu/etd2/953
Rights Statement
