Neovascularization of ischemic tissues by gene delivery of the extracellular matrix protein Del-1
Jingping Zhong, Brian Eliceiri, Dwayne Stupack, Kalyani Penta, Gordon Sakamoto, Thomas Quertermous, Mike Coleman, Nancy Boudreau, Judith A. Varner
Jingping Zhong, Brian Eliceiri, Dwayne Stupack, Kalyani Penta, Gordon Sakamoto, Thomas Quertermous, Mike Coleman, Nancy Boudreau, Judith A. Varner
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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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Integrin αvβ5 is required for Del-1– but not bFGF-mediated angiogenesis....
Integrin αvβ5 is required for Del-1– but not bFGF-mediated angiogenesis. (a) Angiogenesis was induced by injection of growth factor–reduced Matrigel containing bFGF or Del-1 in homozygous integrin β5-null (β5–/–) mice and age-matched heterozygous (β5+/–) sibling mice as well as β5+/+ mice. Cryosections of Matrigel plugs were immunostained with Ab’s directed against murine CD31. (b) CD31-positive vessels were quantified in five ×200 microscopic fields per plug, and the mean ± SEM for each treatment group was determined. Asterisk indicates statistically significant result relative to wild-type controls (P < 0.001). (c) Angiogenesis was induced by injection of growth factor–reduced Matrigel containing bFGF or Del-1 in homozygous integrin β3-null (β3–/–) mice, age- and strain-matched C57BL/6 × 129S F2 hybrid β3-positive mice (F2), as well as age-matched β3-positive C57BL/6 mice (C57). Cryosections of Matrigel plugs were immunostained with Ab’s directed against murine CD31. (d) CD31-positive vessels were quantified in five ×200 microscopic fields per plug and the mean × SEM for each treatment group was determined. Asterisk indicates statistically significant result relative to wild-type controls (P < 0.001).