Graduation Year
2024
Document Type
Dissertation
Degree
Ph.D.
Degree Name
Doctor of Philosophy (Ph.D.)
Degree Granting Department
Medical Sciences
Major Professor
Ying Yang, Ph.D.
Committee Member
Jerome Breslin, Ph.D.
Committee Member
George E. Davis, Ph.D.
Committee Member
Mack Wu, Ph.D.
Committee Member
Lianchun Wang, Ph.D.
Keywords
Rictor, mTORC2, Oscillatory shear stress, Mechano-transduction, Vascular biology
Abstract
The lymphatic vasculature maintains tissue fluid homeostasis by absorbing interstitial fluid to form lymph and transporting it back to the bloodstream. Collecting lymphatic vessels have lymphatic valves (LVs) that prevent the retrograde flow of lymph generated by hydrostatic pressure from the blood vasculature. Backflow and accumulation of lymph leads to a lymphatic pathology called lymphedema. This implicates the involvement of defective LVs in the pathogenesis of lymphedema and warrants the study of lymphatic valve development and maintenance. The LVs are formed through a process called mechanotransduction which signals through the intracellular PI3K-AKT pathway in lymphatic endothelial cells. However, the activation of AKT in response to shear stress outside the cell is yet to be determined. Here, we show that the genetic deletion of Rictor, a mTORC2 protein upstream of AKT, in mouse lymphatic endothelial cells, results in the loss of LVs and smooth muscle cells coverage on collecting lymphatic vessels compared to the control. We also show that Rictor knockdown in vitro in lymphatic endothelial cells downregulates the ex-pression of valve genes, and flow response genes, and attenuates AKT signaling even in the pres-ence of oscillatory shear stress. We further show that Rictor deletion in LECs, both in vivo and in vitro, leads to increased nuclear FOXO1, which is a potent lymphatic valve repressor. Hence, we were able to rescue the loss of valves and smooth muscle cells by LEC-specific double deletion of Rictor and Foxo1. In conclusion, we discovered a novel role of Rictor in the regulation of lymphat-ic valve formation and maintenance through the AKT-FOXO1 signaling axis.
Scholar Commons Citation
Banerjee, Richa, "Rictor, a mTORC2 Protein, Regulates Lymphatic Valve Formation and Maintenance Through the AKT-FOXO1 Signaling Axis" (2024). USF Tampa Graduate Theses and Dissertations.
https://digitalcommons.usf.edu/etd/10594
