A novel adenoviral gutless vector encoding sphingosine kinase promotes arteriogenesis and improves perfusion in a rabbit hindlimb ischemia model.
OBJECTIVE
We previously demonstrated that sphingosine kinase (SPK) increases the level of extracellular sphingosine-1-phosphate and promotes neovascularization in a mouse matrigel model. In this study, we tested the hypothesis that SPK gene transfer using a novel adenoviral 'gutless' vector (AGV) can enhance arteriogenesis in a rabbit hindlimb ischemia model.


METHODS
Thirty-five male New Zealand white rabbits were randomized to the AGV-SPK group (n=13), AGV-null group (n=13), and control group (n=9). On day 10, after the induction of unilateral hindlimb ischemia, gene vectors or buffer were introduced and the effect examined on day 30, using calf blood pressure, quantitative angiographic analysis, and histology.


RESULTS
Calf systolic blood pressure ratios of the ischemic limb to the normal limb on day 30 were 0.77+/-0.13 in control groups, including the AGV-null group, and 0.91+/-0.14 in the AGV-SPK group (P<0.05). Angiographic vessel counts were significantly increased (8.0+/-2.1 at baseline and 11.8+/-3.2 on day 30, P<0.001) in the AGV-SPK group. Histologic analysis showed that microscopic total vessel counts on day 30 were 3.5+/-1.8/field in the control and AGV-null group and 5.4+/-1.0/field in the AGV-SPK group. Arterioles (AGV-SPK; 3.0+/-0.8 versus control and AGV-null; 2.1+/-1.1, P<0.05) were significantly increased in the AGV-SPK group.


CONCLUSIONS
This study shows that SPK promotes arteriogenesis, as evidenced by the maximal improvement in the blood pressure restoration and collateral vessel counts. SPK may be an important angiogenic target to improve perfusion in ischemic tissues.
Lee
Jae Ung
JU
Weill Cornell Medical College of Cornell University, New York 10021, USA.
Shin
Jinho
J
Song
Woohyuk
W
Kim
Hyunjoong
H
Lee
Seunghwan
S
Jang
Se Jin
SJ
Wong
S Chiu
SC
Edelberg
Jay E
JE
Liau
Gene
G
Hong
Mun K
MK
D000256:Adenoviridae / Q000235:genetics; D043925:Angiogenesis Inducing Agents / Q000378:metabolism* / Q000627:therapeutic use; D000792:Angiography; D000818:Animals; D005263:Femoral Artery / Q000187:drug effects / Q000254:growth & development; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000096:biosynthesis; D006614:Hindlimb / Q000098:blood supply; D007511:Ischemia / Q000188:drug therapy*; D008297:Male; D023421:Models, Animal; D018919:Neovascularization, Physiologic / Q000187:drug effects; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics / Q000378:metabolism* / Q000627:therapeutic use; D011817:Rabbits; D012039:Regional Blood Flow / Q000187:drug effects; D000099157:Sphingosine Kinase
D043925:Angiogenesis Inducing Agents; D017853:Phosphotransferases (Alcohol Group Acceptor); D000099157:Sphingosine Kinase