Graduation Year
2023
Document Type
Dissertation
Degree
Ph.D.
Degree Name
Doctor of Philosophy (Ph.D.)
Degree Granting Department
Medical Sciences
Major Professor
Joshua P. Scallan, Ph.D.
Committee Member
Jerome Breslin, Ph.D.
Committee Member
George E. Davis, MD, Ph.D.
Committee Member
Patricia Kruk, Ph.D.
Keywords
Lymphedema, Mechanotransduction, Nitric Oxide Synthase, Shear stress, β-catenin
Abstract
Lymphedema is a disease that occurs when lymph flow is impaired, resulting in tissue swelling, fibrosis, chronic inflammation and recurrent secondary infections. Lymphatic valves play a critical role in maintaining unidirectional lymph flow and evidence for valve defects have been reported in lymphedema patients. The lack of drugs that can correct lymphatic valve defects warrants a better understanding of the molecular regulators of lymphatic valve development and maintenance. Lymphatic valves first develop during embryogenesis in response to mechanotransduction signaling pathways triggered by oscillatory lymph flow. Since eNOS (gene name: Nos3) is a well characterized mechanotransduction signaling molecule in blood vessels, we studied the role of eNOS in lymphatic valve development. We show that Nos3-/- mice experience a delay in lymphatic valve formation due to a defect in valve specification during embryonic development. We further show that eNOS regulates valve specification by forming a complex with the transcription factor β-catenin to regulate its activity. Genetic expression of a β-catenin gain-of-function allele was unable to rescue the loss of valves in Nos3-/- embryos, supporting that eNOS is required for nuclear translocation of β-catenin to promote its transcriptional activity. OSS-induced AKT signaling was previously shown to regulate lymphatic valve formation by attenuating FOXO1-mediated repression of valve gene expression and, consistent with this, we show that genetic deletion of FOXO1 rescued valve formation in Nos3-/- embryos. In conclusion, we demonstrate a novel, nitric oxide-independent role for eNOS in regulating lymphatic valve specification and propose a mechanism by which eNOS forms a complex with β-catenin to regulate its transcriptional activity.
Scholar Commons Citation
Iyer, Drishya, "A Novel Role for eNOS in Regulating Lymphatic Valve Development During Embryogenesis" (2023). USF Tampa Graduate Theses and Dissertations.
https://digitalcommons.usf.edu/etd/9977
