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

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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Hox D3 is required for Del-1–induced angiogenesis. (a) CAMs of 10-day-ol...
Hox D3 is required for Del-1–induced angiogenesis. (a) CAMs of 10-day-old chicken embryos stimulated by PBS, bFGF, or Del-1 were transfected with either N1-GFP reporter vector or Hox D3 sense (S), or Hox D3 antisense (AS) DNA expression constructs and N1-GFP. CAMs were fixed prior to excision, and blood vessel branch points (vessel branch pts) were quantified. (b) Expression levels of the chicken (chick) Hox D3, human Hox D3, and chicken GADPH genes in treated CAM tissues were determined by RT-PCR. (c and d) Relative levels of chick Hox D3 (c) and human Hox D3 (d). PCR products were determined by densitometry in comparison with GADPH expression levels for each treatment. (e) Expression levels of integrin β3 and β5, as well as GFP in CAMs stimulated with Del-1 or bFGF and treated with saline (PBS), Hox D3 antisense or sense were determined by Western blot analysis. Average expression levels for each integrin were determined in three separate experiments by densitometry. Asterisks indicate statistical significance relative to bFGF or Del-1 stimulation (P < 0.01).