Vascular wall maturation and prolonged angiogenic effect by endothelial-specific platelet-derived growth factor expression.
BACKGROUND
The implementation of angiogenic gene therapy at clinics is hindered by the transience of the therapeutic effect. Recruiting vascular wall smooth muscle cells, a process termed 'maturation', can stabilize newly formed vessels.


OBJECTIVE
To induce angiogenesis followed by vessel maturation in a murine ischemic limb model by endothelial cell-specific promoter regulated expression of vascular endothelial growth factor (VEGF) and platelet-derived growth factor-BB (PDGF-BB).


METHODS
We constructed adenoviral vectors containing angiogenic factors VEGF and PDGF-B regulated by a modified preproendothelin-1 (PPE-1-3x) promoter and investigated their angiogenic effect in a murine ischemic limb model.


RESULTS
VEGF gene therapy increased perfusion and the vessel density in the limb shortly after expression with PPE-1-3x promoter or cytomegalovirus (CMV) promoter vectors, but only PPE-1-3xVEGF treatment exhibited a sustained effect. Expression of PDGF-B by PPE-1-3x promoter resulted in morphological maturation of the vasculature and further increased the perfusion, while nonspecific expression of PDGF-B with CMV promoter had no therapeutic effect. Regulation of dual therapy with VEGF and PDGF-B by PPE-1-3x promoter resulted in an early-onset, sustained angiogenic effect accompanied by vessel maturation.


CONCLUSIONS
Systemic gene therapy with the angiogenic factors VEGF and PDGF-B under angiogenic- endothelial cell-specific regulation was effective in inducing functionally and morphologically mature vasculature.
Levanon
Keren
K
Institute of Lipids and Atherosclerosis Research, Sheba Medical Center, Tel Hashomer, Israel.
Varda-Bloom
Nira
N
Greenberger
Shoshana
S
Barshack
Iris
I
Goldberg
Iris
I
Orenstein
Arie
A
Breitbart
Eyal
E
Shaish
Aviv
A
Harats
Dror
D
D000256:Adenoviridae / Q000235:genetics; D043925:Angiogenesis Inducing Agents / Q000378:metabolism; D000818:Animals; D000077214:Becaplermin; D004195:Disease Models, Animal; D019332:Endothelin-1 / Q000235:genetics / Q000378:metabolism; D004730:Endothelium, Vascular / Q000378:metabolism* / Q000473:pathology; D005260:Female; D015316:Genetic Therapy; D005822:Genetic Vectors; D006614:Hindlimb / Q000098:blood supply / Q000473:pathology / Q000601:surgery; D007150:Immunohistochemistry; D007511:Ischemia / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D009131:Muscle, Smooth, Vascular / Q000378:metabolism* / Q000473:pathology; D018919:Neovascularization, Physiologic / Q000235:genetics*; D010982:Platelet-Derived Growth Factor / Q000235:genetics* / Q000378:metabolism; D020574:Proto-Oncogene Proteins c-sis; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
D043925:Angiogenesis Inducing Agents; D019332:Endothelin-1; D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D000077214:Becaplermin