Methods for enhancing vascular density

Abstract

The present invention relates to methods of increasing vascular density and/or blood flow in tissue of a subject, and to increasing exercise capacity of a subject, the methods include administering to a subject an effective amount of an agent that elevates SIRT1 activity in endothelial cells of the subject, the invention further includes administering an NAD+ agonist or NAD+ precursor to a subject to increase vascular density and/or blood flow. The invention includes compositions comprising the said agent.

1 . A method of increasing vascular density and/or blood flow and/or angiogenesis and/or neovascularisation in tissue of a subject, and/or exercise capacity of a subject, comprising administering to the subject an effective amount of an agent which elevates SIRT1 activity or SIRT1 expression in endothelial cells of the subject. 
     
     
         2 - 9 . (canceled) 
     
     
         10 . The method of  claim 1 , wherein increasing vascular density and/or blood flow in tissue of a subject, and/or increasing exercise capacity in a subject, comprises:
 (a) subjecting the subject to exercise training over an exercise training period; and   (b) administering to the subject an effective amount of an agent which elevates SIRT1 activity or SIRT1 expression in endothelial cells of the subject before and/or during the exercise training period.   
     
     
         11 . The method of  claim 10 , wherein the agent is an NAD+ precursor before and/or during the exercise training period. 
     
     
         12 - 13 . (canceled) 
     
     
         14 . The method of  claim 10 , wherein the NAD +  agonist is an agent which raises NAD +  levels in endothelial cells of the subject. 
     
     
         15 . The method of  claim 14 , wherein the agent which raises NAD +  levels in an endothelial cell of the subject comprises an NAD +  precursor. 
     
     
         16 . The method of  claim 15 , wherein the NAD+ precursor is NMN or a pharmaceutically acceptable salt thereof, NR or a pharmaceutically acceptable salt thereof, NaR or a pharmaceutically acceptable salt thereof, NAAD or a pharmaceutically acceptable salt thereof, or NaMN or a pharmaceutically acceptable salt thereof. 
     
     
         17 . The method of  claim 1 , wherein the agent is administered in combination with a H 2 S precursor. 
     
     
         18 - 19 . (canceled) 
     
     
         20 . The method of  claim 17 , wherein the H 2 S precursor is sodium hydrosulfide, or a pharmaceutically acceptable salt thereof, or GYY4137 or a pharmaceutically acceptable salt thereof. 
     
     
         21 . The method of  claim 1 , wherein the increase in vascular density is an increase in microvascular density and/or an increase in capillary density. 
     
     
         22 . (canceled) 
     
     
         23 . The method of  claim 1 , wherein the tissue is muscle. 
     
     
         24 . (canceled) 
     
     
         25 . The method of  claim 1 , wherein the subject is an aged subject. 
     
     
         26 . The method of  claim 1 , wherein the agent, NAD+ agonist or NAD+ precursor is administered orally. 
     
     
         27 . A method of treating or preventing a disease or condition selected from the group consisting of: coronary and/or peripheral arterial disease; ischaemia; ulcers; lung disease; pulmonary hypertension; frailty; sarcopenia; neurodegenerative disease, such as vascular dementia; stroke; haemorrhage; osteoporosis; heart disease; and vascular disease, in a subject, comprising administering to the subject an effective amount of an agent which elevates SIRT1 activity or SIRT1 expression in endothelial cells of the subject. 
     
     
         28 - 40 . (canceled) 
     
     
         41 . A method of:
 increasing vascular density in tissue of a subject having reduced mobility;   increasing exercise capacity in subjects having reduced mobility;   enhancing liver sinusoidal endothelial cell function in a subject;   enhancing the physical performance of a subject;   enhancing the effects of exercise in a subject;   improving vascular recovery in a subject following injury or immobilisation;   enhancing benefits of physiotherapy in a subject;   increasing endurance in a subject;   enhancing blood flow to the eyes of a subject;   enhancing skin appearance of a subject;   increasing vitality of an aged subject   enhancing meat production in an animal; or   enhancing the performance of a racing animal,   comprising administering to the subject an effective amount of an NAD +  agonist.   
     
     
         42 . The method of  claim 41 , wherein the NAD+ agonist is an NAD+ precursor. 
     
     
         43 . (canceled) 
     
     
         44 . A composition for increasing vascular density and/or blood flow and/or exercise capacity in a subject, comprising an NAD+ precursor and optionally a H 2 S precursor. 
     
     
         45 . A virus comprising a viral vector, wherein the viral vector comprises nucleic acid for increasing vascular density and/or blood flow in tissue of a subject, and/or exercise capacity of a subject, wherein the nucleic acid comprises a coding sequence which encodes:
 (a) SIRT1 protein;   (b) one or more NAD+ biosynthetic enzymes, or   (c) an NAMPT, NMNAT1, NMNAT2, and/or NMNAT3 miRNA antagonist.   
     
     
         46 - 52 . (canceled) 
     
     
         53 . The method of  claim 41 , wherein the method is for increasing vitality of an aged subject, and the subject is a companion animal or pet. 
     
     
         54 - 56 . (canceled) 
     
     
         57 . A method of reducing:
 (a) lack of coordination;   (b) extreme fatigue and lethargy;   (c) loss of appetite;   (d) decline or worsening of an existing condition;   (e) slow healing of wounds; or   (f) the onset of age-related diseases,   
       in an aged subject, comprising administering to the subject an effective amount of an NAD precursor. 
     
     
         58 - 59 . (canceled) 
     
     
         60 . The method of  claim 53 , wherein the aged subject is a dog. 
     
     
         61 . The method of  claim 1 , wherein the subject is a human. 
     
     
         62 . The method of  claim 1 , wherein the subject is a non-human. 
     
     
         63 . The method of  claim 27 , wherein the agent comprises an NAD +  precursor. 
     
     
         64 . The method of  claim 27 , wherein the agent is administered in combination with a H 2 S precursor.