VEGF trap abolishes shear stress- and overload-dependent angiogenesis in skeletal muscle.
OBJECTIVE
To determine which elements of the angiogenic process are controlled by VEGF under physiological conditions.


METHODS
VEGF Trap was administered at 10 mg x kg(-1) by subcutaneous injection twice weekly to mice, which were subject to one of two established angiogenic stimuli: (1) increasing blood flow by administration of prazosin (50 mg L(-1)); (2) muscle overload by extirpation of a synergist. Angiogenesis was determined by calculating capillary to fiber ratio (C:F), and proliferating cell nuclear antigen (PCNA) staining localized to capillaries or the interstitium used to measure cell proliferation. Characteristic ultrastructural changes were quantified using electron microscopy.


RESULTS
Administration of VEGF Trap abolished the increases in C:F seen in both models, and prevented growth of luminal filopodia and large vacuole formation. Overload-induced proliferation associated with capillaries was reduced, along with endothelial cell number abluminal sprouts and basement membrane breakage. However, interstitial proliferation remained high, along with the increased capillary association of pericytes and fibroblasts.


CONCLUSIONS
VEGF is required for both models of angiogenesis, although some morphological changes lie upstream, or are independent of, VEGF involvement. The abolition of angiogenesis in a model unaffected by NO inhibition shows that NO is not required for all VEGF-dependent angiogenesis in vivo.
Williams
James L
JL
Angiogenesis Research Group, Centre for Cardiovascular Sciences, University of Birmingham, Birmingham, UK.
Cartland
David
D
Rudge
John S
JS
Egginton
Stuart
S
D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D005347:Fibroblasts / Q000378:metabolism; D008297:Male; D051379:Mice; D018482:Muscle, Skeletal / Q000098:blood supply* / Q000378:metabolism; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D009569:Nitric Oxide / Q000378:metabolism; D020286:Pericytes / Q000378:metabolism; D011224:Prazosin / Q000494:pharmacology; D017978:Receptors, Growth Factor; D011993:Recombinant Fusion Proteins / Q000494:pharmacology*; D013314:Stress, Mechanical; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
D017978:Receptors, Growth Factor; D011993:Recombinant Fusion Proteins; C460365:VEGF Trap R1R2 protein; D042461:Vascular Endothelial Growth Factor A; D009569:Nitric Oxide; D011224:Prazosin