Early ReportClinical evidence of angiogenesis after arterial gene transfer of phVEGF165 in patient with ischaemic limb
Introduction
Among the growth factors that promote angiogenesis, vascular endothelial growth factor (VEGF),2 also known as vascular permeability factor,3 and vasculotropin,4 is specifically mitogenic for endothelial cells. The first exon of the VEGF gene includes a secretory signal sequence that permits the protein to be secreted naturally from intact cells.5 We have shown6, 7 that arterial gene transfer of naked DNA encoding for secreted protein yielded physiological levels of protein despite low transfection efficiency. Site-specific gene transfer of plasmid DNA encoding the 165-aminoacid isoform of human VEGF (phVEGF 165) applied to the hydrogel polymer coating of an angioplasty balloon,8 and delivered percutaneously to the iliac artery of rabbits in which the femoral artery had been excised to cause unilateral hindlimb ischaemia led to development of collateral vessels and increased capillary density, improved calf blood-pressure ratio (ischaemic/normal limb) and increased resting and maximum vasodilator-induced blood flow.9, 10 We now use this strategy in the ischaemic limb of a patient.
Section snippets
Patient
A 70-year-old non-diabetic woman was referred for gangrene of the right great toe. About a year earlier, the patient had cramping right-foot pain; several corns were removed, she was given intramuscular cortisone, prescribed ibuprofen, and fitted with shoe inserts. Symptoms worsened and the patient received oxycodone, hydrocodone, and a fentanyl patch. The great toe lesion progressed to gangrene, and the second and third toes became compromised. She had no palpable pedal pulses of the right
Results
Intravascular ultrasound immediately before gene transfer showed that the intended site, the distal popliteal artery, was free of atherosclerotic plaque that might compromise transfection efficiency.12 The arterial wall had a clearly recognisible three-layer appearance with no intimal thickening.13 Repeat ultrasound at 4 weeks and 12 weeks after gene transfer disclosed no neointimal thickening resulting from inflation of the hydrogel-coated angioplasty-balloon-catheter (figure 1).
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Discussion
Beginning with Nabel et al,15 several laboratories showed the feasibility of arterial gene transfer in animal models. In December, 1994, we began a dose-escalating clinical trial.11 Doses of 100 and 500 μg of phVEGF165 administered to one patient each were inactive. 1000 μg improved lower extremity blood-flow in three of five patients, revealed by intravascular doppler analysis and magnetic resonance imaging. Contrast angiography, however, disclosed no new collateral vessels. DNA-labelling
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2022, Microvascular ResearchCitation Excerpt :The two RTKs that have been shown to regulate blood vessel formation during embryogenesis when combined with their ligand VEGF are fetal liver kinase receptor-1 (Flk-1), also known as Vascular endothelial growth factor receptor-2 (VEGFR2), and Fms-related tyrosine kinase-1 (Flt-1), also known as VEGF receptor-1 (VEGFR1) (Fong et al., 1995; Takeshita et al., 1994). It has been shown that this receptor/ligand system boosts neovascularization (Asahara et al., 1998; Banai et al., 1994; Isner et al., 1996). VEGF is an endothelial cell-specific angiogenic factor and a key regulator of angiogenesis, stimulating endothelial cell proliferation, migration, and proteolytic action (Maruyama et al., 1999).