Methods of modulating angiogenesis via trpv4

Abstract

The present invention relates to methods of inhibiting capillary endothelial (CE) cell migration, the formation of CE networks and angiogenesis, and uses thereof for the purpose of treating angiogenesis-related diseases and disorders, particularly when the diseases or disorders are directly related aberrant angiogenesis. Inhibition is achieved by inhibiting TRPV4 activity, such as the levels of TRPV4 expression, calcium influx through TRPV4, and/or the intracellular signaling from TRPV4 via β1 integrin activation.

What is claimed: 
     
         1 . A method for inhibiting endothelial cell migration, the method comprising contacting an endothelial cell with a TRPV4 inhibitor. 
     
     
         2 . The method of  claim 1 , wherein the TRPV4 inhibitor is selected from the group consisting of an antibody, an RNA interference molecule, a small molecule, a peptide and an aptamer. 
     
     
         3 . The method of  claim 2 , wherein the TRPV4 inhibitor inhibits an influx of calcium into the cell. 
     
     
         4 . The method of  claim 2 , wherein the TRPV4 inhibitor is an RNA interference molecule that inhibits TRPV4 expression in the cell. 
     
     
         5 . The method of  claim 4 , wherein the TRPV4 inhibitor is an siRNA directed specifically against a TRPV4 gene. 
     
     
         6 . The method of  claim 2 , wherein the TRPV4 inhibitor inhibits a phosphorylation of β1 integrin in the cell. 
     
     
         7 . The method of  claim 2 , wherein the TRPV4 inhibitor inhibits a phosphorylation of AKT in the cell. 
     
     
         8 . The method of  claim 2 , wherein the TRPV4 inhibitor is an antibody directed specifically against a β1 integrin. 
     
     
         9 . The method of  claim 1 , wherein the endothelial cell is a mammalian endothelial cell. 
     
     
         10 . The method of  claim 1 , wherein the mammalian endothelial cell is a human endothelial cell. 
     
     
         11 . A method for inhibiting endothelial cell migration, the method comprising contacting an endothelial cell with an antibody directed specifically against a β1 integrin, wherein the integrin function is blocked by the antibody. 
     
     
         12 . The method of  claim 11 , wherein the antibody is a monoclonal antibody derived from clone P5D2. 
     
     
         13 . A method for inhibiting angiogenesis in a mammal in need thereof, the method comprising administering a therapeutically effective amount of a TRPV4 inhibitor and a pharmaceutically acceptable carrier. 
     
     
         14 . The method of  claim 13 , wherein the TRPV4 inhibitor is selected from the group consisting of an antibody, an RNA interference molecule, a small molecule, a peptide and an aptamer. 
     
     
         15 . The method of  claim 13 , wherein the mammal is afflicted with an angiogenesis-related disease or disorder. 
     
     
         16 . The method of  claim 15 , wherein the angiogenesis-related disease is selected from the group consisting of cancer, macular degeneration; diabetic retinopathy; rheumatoid arthritis; Alzheimer's disease; obesity, psoriasis, atherosclerosis, vascular malformations, angiomata, and endometriosis. 
     
     
         17 . The method of  claim 13 , wherein the mammal is a human. 
     
     
         18 . The method of  claim 13 , wherein an anti-angiogenic therapy is administered in conjunction with the method. 
     
     
         19 . The method of  claim 13 , wherein a chemotherapy and/or radiation therapy is administered in conjunction with the method.