Neovascularization of ischemic tissues by gene delivery of the extracellular matrix protein Del-1.
The ECM protein Del-1 is one of several novel ECM proteins that accumulate around angiogenic blood vessels in embryonic and tumor tissue and promote angiogenesis in the absence of exogenous growth factors. Del-1 expressed in mouse or rabbit ischemic hind-limb muscle by gene transfer rapidly promotes new blood vessel formation and restores muscle function. This angiogenic ECM protein initiates angiogenesis by binding to integrin alphavbeta5 on resting endothelium, thereby resulting in expression of the transcription factor Hox D3 and integrin alphavbeta3. Hox D3 converts resting endothelium to angiogenic endothelium by inducing expression of proangiogenic molecules such as integrin alphavbeta3. These findings provide evidence for an angiogenic switch that can be initiated in the absence of exogenous growth factors and indicate that the angiogenic matrix protein Del-1 may be a useful tool for the therapy of ischemic disease.
Zhong
Jingping
J
Comprehensive Cancer Center, University of California, San Diego, La Jolla, California 92093-0912, USA.
Eliceiri
Brian
B
Stupack
Dwayne
D
Penta
Kalyani
K
Sakamoto
Gordon
G
Quertermous
Thomas
T
Coleman
Mike
M
Boudreau
Nancy
N
Varner
Judith A
JA
D000818:Animals; D002135:Calcium-Binding Proteins; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D015815:Cell Adhesion Molecules; D004268:DNA-Binding Proteins; D016228:Endothelial Growth Factors / Q000235:genetics; D015316:Genetic Therapy; D006614:Hindlimb / Q000098:blood supply; D018398:Homeodomain Proteins / Q000235:genetics; D016023:Integrins / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics; D007511:Ischemia / Q000503:physiopathology / Q000628:therapy*; D008222:Lymphokines / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018919:Neovascularization, Physiologic; D019030:Receptors, Vitronectin / Q000378:metabolism; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D002135:Calcium-Binding Proteins; D002352:Carrier Proteins; D015815:Cell Adhesion Molecules; D004268:DNA-Binding Proteins; C491706:Edil3 protein, mouse; D016228:Endothelial Growth Factors; D018398:Homeodomain Proteins; C484113:Hoxd3 protein, mouse; D016023:Integrins; D036341:Intercellular Signaling Peptides and Proteins; D008222:Lymphokines; D019030:Receptors, Vitronectin; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; C064660:integrin alphaVbeta5; C073547:HOXA4 protein, human