Compounds and Methods for Modulating Vascular Injury

Abstract

Methods of modulating healing response to vascular injury and/or vascular scarring in a subject are provided. As such, aspects of the disclosure relate to the use of pro-resolving lipid mediators to modulate inflammation and/or restenosis of a vascular wall. Another aspect of the disclosure relates to the use of pro-resolving lipid mediators to modulate a biological activity of vascular smooth muscle cells (VSMC) or vascular endothelial cells (VEC). Pro-resolving lipid mediators that find use in the subject methods include derivatives of omega-3 polyunsaturated fatty acids and omega-6 polyunsaturated fatty acids, such as resolvins, protectins, lipoxins and maresins and their therapeutically stable analogs. Also provided are vascular devices and compositions for use in the subject methods. Such methods, devices and compositions find use in a variety of applications, including applications related to treatment of vascular injuries and vascular scarring (e.g., restenosis), and applications related to chronic inflammatory diseases of the vascular wall .

1 . A method of modulating a response to vascular injury or scarring of a vascular wall, the method comprising:
 contacting the vascular wall with a pro-resolving lipid mediator in an amount sufficient to modulate the response to the vascular injury or scarring of the vascular wall.   
     
     
         2 . The method of  claim 1 , wherein the pro-resolving lipid mediator is a hydroxylated derivative of an omega-3 polyunsaturated fatty acid or an omega-6 polyunsaturated fatty acid. 
     
     
         3 . The method of  claim 2 , wherein the omega-3 polyunsaturated fatty acid is eicosapentaenoic acid (EPA) and the pro-resolving lipid mediator is a hydroxylated derivative of EPA. 
     
     
         4 . The method of  claim 2 , wherein the omega-6 polyunsaturated fatty acid is docosahexaenoic acid (DHA) and the pro-resolving lipid mediator is a hydroxylated derivative of DHA. 
     
     
         5 . The method of  claim 1 , wherein the pro-resolving lipid mediator is selected from the group consisting of resolvins, maresins, protectins, precursors thereof, and derivatives thereof. 
     
     
         6 . The method of  claim 1 , wherein the pro-resolving lipid mediator is a D-series resolvin or an E-series resolvin. 
     
     
         7 . The method of  claim 1 , wherein the pro-resolving lipid mediator is a Maresin. 
     
     
         8 . (canceled) 
     
     
         9 . The method of  claim 1 , wherein the method resolves vascular wall inflammation. 
     
     
         10 . The method of  claim 1 , wherein method reduces restenosis of the vascular wall. 
     
     
         11 . The method of  claim 6 , wherein the D-series resolvin is a dihydroxylated or a trihydroxylated derivative of docosahexaenoic acid (DHA). 
     
     
         12 . (canceled) 
     
     
         13 . The method of  claim 6 , wherein the D-series resolvin is described by formula (I):
   HO 2 C—CH 2 —CH 2 -L-CH(OH)—CH 2 —CH═CH—CH 2 —CH 3    (I)
   wherein L is a linear C13 hydrocarbon chain comprising:
 five —CH═CH— groups; and 
 three groups independently selected from: —CH 2 —, —(C═O)— and —CH(OH)—. 
   
     
     
         14 . The method of  claim 13 , wherein the D-series resolvin has a 17(S) configuration. 
     
     
         15 . The method of  claim 13 , wherein when one or more of the five —CH═CH— groups is present at a position selected from the 4, 7, 10, 13 or 19 positions, the —CH═CH— group at the position has a Z-configuration or wherein when one or more of the five —CH═CH— groups is present at a position selected from the 5, 6, 8, 9, 11, 12 or 14 positions, the —CH═CH— group at the position has an E-configuration. 
     
     
         16 . (canceled) 
     
     
         17 . The method of  claim 13 , wherein L comprises two —CH(OH)— groups and one —CH 2 — group. 
     
     
         18 . The method of  claim 13 , wherein L comprises three —CH═CH— groups in the E-configuration and two —CH═CH— groups in the Z-configuration. 
     
     
         19 . The method of  claim 18 , wherein L comprises the following group: 
       
         
           
           
               
               
           
         
       
     
     
         20 - 22 . (canceled) 
     
     
         23 . The method of  claim 13 , wherein the D-series resolvin is RvD1, RvD2, RvD3 or RvD4. 
     
     
         24 - 66 . (canceled) 
     
     
         67 . A D-series resolvin- or Maresin-containing vascular device for modulating a response to vascular injury or vascular scarring of a vascular wall. 
     
     
         68 . The device of  claim 67 , wherein the D-series resolvin is described by formula (I):
   HO 2 C—CH 2 —CH 2 -L-CH(OH)—CH 2 —CH═CH—CH 2 —CH 3    (I)
   wherein L is a linear C13 hydrocarbon chain comprising:
 five —CH═CH— groups; and 
 three groups independently selected from: —CH 2 —, —(C═O)— and —CH(OH)—. 
   
     
     
         69 - 70 . (canceled)