Vascular endothelial growth factor stimulates angiogenesis without improving collateral blood flow following hindlimb ischemia in rabbits.
This study was designed to test the ability of adenovirus-delivered vascular endothelial growth factor (Ad-VEGF) to stimulate angiogenesis and arteriogenesis in the rabbit hindlimb following the induction of ischemia and to evaluate the functional changes in the collateral circulation. Ten days after the surgical induction of hindlimb ischemia, either a control virus (1 x 10(9) pfu) or an adenovirus containing the gene for VEGF(165) (1 x 10(6), 1 x 10(7), 1 x 10(8), or 1 x 10(9) pfu) was administered intramuscularly into the ischemic limb. Thirty days after administration of the adenoviral vectors, skeletal muscle capillary density was assessed and angiography was performed as markers of angiogenesis and arteriogenesis, respectively. Hindlimb blood flow was directly measured and hyperemic tests were performed to evaluate the functional improvements in collateral blood flow. Animals treated with Ad-VEGF at 1 x 10(8) and 1 x 10(9) pfu showed elevated levels of circulating VEGF and dose-dependent hindlimb edema. These doses also led to a robust angiogenic response (i.e., increase in capillary density), but failed to improve collateral blood flow. Consistent with the lack of a functional response, there was no angiographic evidence of enhanced arteriogenesis with any dose of Ad-VEGF. Following the induction of hindlimb ischemia, administration of Ad-VEGF stimulated capillary sprouting (i.e., angiogenesis), but did not increase the growth and development of larger conduit vessels (i.e., arteriogenesis) or improve collateral blood flow. These results support the concept that VEGF may not be expected to have therapeutic utility for the treatment of peripheral or myocardial ischemia.
Hershey
James C
JC
Department of Pharmacology, Merck Research Laboratories, Merck & Co, Inc., WP46-200, West Point, PA 19454, USA. james_hershey@merck.com
Baskin
Elizabeth P
EP
Corcoran
Halea A
HA
Bett
Andrew
A
Dougherty
Nancy M
NM
Gilberto
David B
DB
Mao
Xianzhi
X
Thomas
Kenneth A
KA
Cook
Jacquelynn J
JJ
D000256:Adenoviridae; D043925:Angiogenesis Inducing Agents / Q000627:therapeutic use*; D000792:Angiography; D000818:Animals; D002196:Capillaries; D003097:Collateral Circulation / Q000187:drug effects*; D006614:Hindlimb / Q000098:blood supply*; D007511:Ischemia / Q000188:drug therapy*; D018482:Muscle, Skeletal / Q000098:blood supply; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D011817:Rabbits; D011897:Random Allocation; D011994:Recombinant Proteins / Q000096:biosynthesis; D012039:Regional Blood Flow; D017211:Treatment Failure; D042442:Vascular Endothelial Growth Factors / Q000378:metabolism* / Q000627:therapeutic use*
D043925:Angiogenesis Inducing Agents; D011994:Recombinant Proteins; D042442:Vascular Endothelial Growth Factors