Repeated, but not single, VEGF gene transfer affords protection against ischemic muscle lesions in rabbits with hindlimb ischemia

Olea, Fernanda Daniela; Janavel, Gustavo Vera; Cuniberti, Luis; Yannarelli, Gustavo; Meckert, Patricia Cabeza; Cors, J; Valdivieso, León; Lev, Gustavo; Mendiz, Oscar; Bercovich, Andrés; Criscuolo, Marcelo; Melo, Cynthia de Freitas; Laguens, Rubén M.; Crottogini, Alberto J.

doi:10.1038/gt.2009.30

Cited by 25 publications

(12 citation statements)

References 38 publications

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“…[34]). However, overall VEGF use in pro-angiogenic therapies has not been effective thus far [35], [36]. Again, use of high GF dose severely limits translation of VEGF use into clinical practice.…”

Section: Discussionmentioning

confidence: 99%

Engineered microenvironments for synergistic VEGF – Integrin signalling during vascularization

et al. 2017

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We have engineered polymer-based microenvironments that promote vasculogenesis both in vitro and in vivo through synergistic integrin-growth factor receptor signalling. Poly(ethyl acrylate) (PEA) triggers spontaneous organization of fibronectin (FN) into nanonetworks which provide availability of critical binding domains. Importantly, the growth factor binding (FNIII12-14) and integrin binding (FNIII9-10) regions are simultaneously available on FN fibrils assembled on PEA. This material platform promotes synergistic integrin/VEGF signalling which is highly effective for vascularization events in vitro with low concentrations of VEGF. VEGF specifically binds to FN fibrils on PEA compared to control polymers (poly(methyl acrylate), PMA) where FN remains in a globular conformation and integrin/GF binding domains are not simultaneously available. The vasculogenic response of human endothelial cells seeded on these synergistic interfaces (VEGF bound to FN assembled on PEA) was significantly improved compared to soluble administration of VEGF at higher doses. Early onset of VEGF signalling (PLCγ1 phosphorylation) and both integrin and VEGF signalling (ERK1/2 phosphorylation) were increased only when VEGF was bound to FN nanonetworks on PEA, while soluble VEGF did not influence early signalling. Experiments with mutant FN molecules with impaired integrin binding site (FN-RGE) confirmed the role of the integrin binding site of FN on the vasculogenic response via combined integrin/VEGF signalling. In vivo experiments using 3D scaffolds coated with FN and VEGF implanted in the murine fat pad demonstrated pro-vascularization signalling by enhanced formation of new tissue inside scaffold pores. PEA-driven organization of FN promotes efficient presentation of VEGF to promote vascularization in regenerative medicine applications.

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Section: Discussionmentioning

confidence: 99%

Engineered microenvironments for synergistic VEGF – Integrin signalling during vascularization

et al. 2017

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“…Gene therapy is established as a potential method to induce therapeutic angiogenesis in ischemic myocardial disease (Ieda et al, 2007;Olea et al, 2009). Non-viral gene transfer represents a safer and less costly method for gene delivery than transfer of viral genes (Hodge et al, 1995).…”

Section: Introductionmentioning

confidence: 99%

A targeted high-efficiency angiogenesis strategy as therapy for myocardial infarction

et al. 2012

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“…However, protection against ischemic muscle lesions in the affected limb was afforded only if the treatment was repeated, the reason being that VEGF expression, and hence the vasculogenic stimulus, decayed steeply after the seventh day post injection. 9 Therefore, we hypothesized that genetically modifying ASCs to overexpress human VEGF 165 would enhance the vasculogenic potential of ASCs, not only by increasing the paracrine angiogenic effect of ASCs but also by attenuating the decay of VEGF expression in the target tissue. In turn, these effects would protect the ischemic muscle against necrotic lesions to a significantly larger extent than nontransfected ASCs.…”

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confidence: 99%

Vascular Endothelial Growth Factor Overexpression Does Not Enhance Adipose Stromal Cell–Induced Protection on Muscle Damage in Critical Limb Ischemia

Olea

Locatelli

Hnatiuk

et al. 2015

ATVB

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Objectives— Critical limb ischemia complicates peripheral artery disease leading to tissue damage and amputation. We hypothesized that modifying adipose stromal cells (ASCs) to overexpress human vascular endothelial growth factor 165 (VEGF) would limit ischemic muscle damage to a larger extent than nonmodified ASCs. Approach and Results— Rabbits with critical hindlimb ischemia were injected with allogeneic abdominal fat-derived ASCs transfected with plasmid-VEGF 165 (ASCs-VEGF; n=10). Additional rabbits received nontransfected ASCs (ASCs; n=10) or vehicle (placebo; n=10). One month later, ASCs-VEGF rabbits exhibited significantly higher density of angiographically visible collaterals and capillaries versus placebo (both P <0.05) but not versus ASCs (both P =NS). Arteriolar density, however, was increased in both ASCs and ASCs-VEGF groups (both P <0.05 versus placebo). ASCs-VEGF and ASCs showed comparable post-treatment improvements in Doppler-assessed peak systolic velocity, blood pressure ratio, and resistance index. Ischemic lesions were found in 40% of the muscle samples in the placebo group, 19% in the ASCs-VEGF group, and 17% in the ASCs groups (both P <0.05 versus placebo, Fisher test). Conclusions— In a rabbit model of critical limb ischemia, intramuscular injection of ASCs genetically modified to overexpress VEGF increase angiographically visible collaterals and capillary density. However, both modified and nonmodified ASCs increase arteriolar density to a similar extent and afford equal protection against ischemia-induced muscle lesions. These results indicate that modifying ASCs to overexpress VEGF does not enhance the protective effect of ASCs, and that arteriolar proliferation plays a pivotal role in limiting the irreversible tissue damage of critical limb ischemia.

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Repeated, but not single, VEGF gene transfer affords protection against ischemic muscle lesions in rabbits with hindlimb ischemia

Cited by 25 publications

References 38 publications

Engineered microenvironments for synergistic VEGF – Integrin signalling during vascularization

Engineered microenvironments for synergistic VEGF – Integrin signalling during vascularization

A targeted high-efficiency angiogenesis strategy as therapy for myocardial infarction

Vascular Endothelial Growth Factor Overexpression Does Not Enhance Adipose Stromal Cell–Induced Protection on Muscle Damage in Critical Limb Ischemia

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