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Neovascularization of ischemic tissues by gene delivery of the extracellular matrix protein Del-1
Jingping Zhong, … , Nancy Boudreau, Judith A. Varner
Jingping Zhong, … , Nancy Boudreau, Judith A. Varner
Published July 1, 2003
Citation Information: J Clin Invest. 2003;112(1):30-41. https://doi.org/10.1172/JCI17034.
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Article Cardiology

Neovascularization of ischemic tissues by gene delivery of the extracellular matrix protein Del-1

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Abstract

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 αvβ5 on resting endothelium, thereby resulting in expression of the transcription factor Hox D3 and integrin αvβ3. Hox D3 converts resting endothelium to angiogenic endothelium by inducing expression of proangiogenic molecules such as integrin αvβ3. 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.

Authors

Jingping Zhong, Brian Eliceiri, Dwayne Stupack, Kalyani Penta, Gordon Sakamoto, Thomas Quertermous, Mike Coleman, Nancy Boudreau, Judith A. Varner

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Figure 2

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Del-1 induces angiogenesis in rabbit model of ischemia. (a) Angiography ...
Del-1 induces angiogenesis in rabbit model of ischemia. (a) Angiography was performed after unilateral hind-limb ischemia induced in New Zealand white rabbits (3–4 kg body weight) by surgical resection of the femoral artery (19). X’s indicate the ten sites in and surrounding the medial thigh (midthigh) (bracket) in the upper leg, where plasmid was injected (0.5 mg/site). (b) Sustained transgene expression induced by plasmid injection in muscle was detected 1 month after therapy by RT-PCR for hVEGF165 and hDel-1. VEGF or Del-1 gene expression was detected in VEGF- or Del-1–plasmid–injected muscle, respectively, but not in control plasmid–injected muscle. MW, molecular weight standards. (c) Angiography was performed before and 1 month after therapy for each treatment. Brackets indicate medial thigh region. (d) Mean number of new vessels (± SD) crossing the medial thigh (area under the brackets in c) for each treatment 1 month after therapy. Asterisks indicate statistically significant result (P < 0.01). (e) Mean CD31 protein expression (± SD) in muscle tissue 1 month after therapy. CD31 levels within injected muscle were assessed by Western blot analysis of lysates of muscle tissue. Asterisks indicate statistically significant result relative to noncoding plasmid control (P < 0.01). Statistical significance for angiography and CD31 analyses was assessed by one-way ANOVA with plasmid treatment as the main effect.
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