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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Figure 3

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Integrin αvβ5 is a receptor for Del-1. (a) Biotinylated Del-1 (Del-1), v...
Integrin αvβ5 is a receptor for Del-1. (a) Biotinylated Del-1 (Del-1), vitronectin (VN), or the 120-kDa cell-binding fragment of fibronectin (FN) immunoblotted with goat–antibiotin HRP. (b–d) Biotinylated Del-1, vitronectin, collagen (COL), or biotinylated 120-kDa cell-binding region of fibronectin incubated with purified integrins αvβ5 (b), αvβ3 (c), or α5β1 (d) were quantified by determining absorbance at 405 nm. (e) FACS profile of HT29 colon carcinoma cells incubated with anti-αvβ5, anti-αvβ3, anti-β1, or no primary Ab (neg) followed by FITC-labeled secondary Ab. Data are plotted as log of fluorescence intensity versus cell number times 10–5. (f) The adhesion of integrin αvβ5-positive/αvβ3-negative HT29 colon carcinoma cells to Del-1 or vitronectin in the presence of culture medium (med), function-blocking anti-integrin Ab’s anti-αvβ3, anti-αvβ5, or anti-integrin β1. (g) FACS profile of HUVECs incubated with anti-αvβ5, anti-αvβ3, or no primary Ab (neg) followed by FITC-labeled secondary Ab, as in e. (h) The adhesion of αvβ5-positive/αvβ3-positive HUVECs on Del-1 or vitronectin in the presence of culture medium, function-blocking anti-integrin Ab’s anti-αvβ3, anti-αvβ5, or anti-integrin α5β1. (i) FACS profile of human microvascular endothelial cells (HMVECs) incubated with anti-αvβ5, anti-αvβ3, or no primary Ab (neg), followed by FITC-labeled secondary Ab, as in e. (j) The adhesion of quiescent HMVECs on Del-1 or vitronectin in the presence of culture medium, function-blocking anti-integrin Ab’s anti-αvβ3, anti-αvβ5, anti-integrin α5β1, or anti-αvβ3 combined with anti-αvβ5 (anti-β3/β5). HPF, high-power field. Magnification, ×200.