miRNA Regulation of Aquaporin 1 Modulates Vascular Remodelling during Cirrhosis

Project: Research project


Cirrhosis and portal hypertension are the cause of significant morbidity, mortality, and healthcare expenditures.
Since hepatic fibrosis and pathological angiogenesis are processes that are mutually dependent and since liver
endothelial cell (LEC) invasion is a requisite step for angiogenesis, studies of the detailed molecular
mechanisms governing LEC invasion are of great importance. LEC invasion is modulated by mechanisms
involving localized cell volume regulation and osmotically driven membrane shape changes. Aquaporin-1
(AQP1) is an integral membrane water channel that is dramatically overexpressed in LEC during cirrhosis and
facilitates invasion through the cirrhotic microenvironment. The precise mechanisms responsible for the
overexpression of AQP1 in LEC during cirrhosis remain largely uninvestigated. Based on selected background
rationale and novel preliminary data, we propose the central hypothesis that local osmotic fluctuation during
cirrhosis drives AQP1 overexpression by altering levels of the osmotically sensitive, AQP1 regulatory miRNAs,
miR-666 and miR-708, thereby promoting dynamic membrane blebbing, LEC invasion, and angiogenesis
during cirrhosis. To accomplish our overall objective, we will employ complementary molecular, cell biologic, an
in vivo approaches to establish the mechanism of AQP1 overexpression and the effect of AQP1 regulatory
miRNAs on LEC invasion, angiogenesis, and cirrhosis. Aim I will focus on how local osmolality silences miR-
666 and miR-708 to subsequently increase AQP1 in LEC. Aim II investigates the effects of miR-666 and miR-
708 on the angiogenic phenotype of LEC. Aim III tests the effects of miR-666 and miR-708 overexpression on
angiogenesis and fibrosis in vivo. The results will mechanistically extend the preliminary findings and provide
novel information regarding the osmotically sensitive, miRNA-based mechanisms, controlling AQP1
overexpression and may ultimately produce the foundation for anti-angiogenic therapies targeting AQP1 and
its molecular regulators in cirrhosis.
Effective start/end date9/13/137/31/18


  • National Institutes of Health: $147,042.00
  • National Institutes of Health: $147,042.00
  • National Institutes of Health: $147,042.00
  • National Institutes of Health: $147,042.00


Aquaporin 1
Endothelial Cells
Vascular Remodeling
Pathologic Neovascularization
Portal Hypertension
Pathologic Processes
Health Expenditures
Ion Channels
Cell Size
Osmolar Concentration


  • Medicine(all)