Capillary enlargement, not sprouting angiogenesis, determines beneficial therapeutic effects and side effects of angiogenic gene therapy

Abstract

Efficient capillary enlargement leading to significant increases in tissue perfusion is needed to gain metabolic benefits after angiogenic gene therapy. However, the risk of systemic side effects can increase as the efficiency of angiogenic gene therapy is improved. Importantly, the unstable wall structure of the newly formed vessels seems not to compromise the metabolic benefits.

Long-term VEGF-A expression promotes aberrant angiogenesis and fibrosis in skeletal muscle

“…15,29 CPS method uses non-linear fundamental frequencies, which results in better spatial resolution and high sensitivity to contrast media, and provides improved tissue subtraction than previous ultrasound perfusion imaging techniques. 30,31 Transversal images of semimembranosus muscles of both limbs were captured after a single bolus (0.5 ml) of SonoVue contrast microbubbles (Bracco, Milan, Italy) with the following parameters at 8.0 MHz: power À16 dB, mechanical index 0.31, CPS gain À10 and depth 20 mm.…”

Long-lasting fibrin matrices ensure stable and functional angiogenesis by highly tunable, sustained delivery of recombinant VEGF 164

“…These results are relevant for the therapeutic potential of α 2 -PI 1-8 -VEGF 164 delivery. In fact, we and others have previously shown that the size of newly induced vessels is key to determine the efficacy of therapeutic angiogenesis approaches (29,30) as a similar increase in number without increase in size provided no therapeutic benefit (29). Based on these considerations, two different α 2 -PI 1-8 -VEGF 164 concentrations in the upper range of normal angiogenesis, 0.5 μg/mL and 5 μg/mL, were chosen to investigate dose-dependent functional improvement in a hind-limb ischemia model.…”

Blunted muscle angiogenic training-response in COPD patientsversussedentary controls

“…The deletion of VEGF-A in the myofibres of transgenic mice dramatically reduced muscle capillarisation and decreased exercise endurance time by ,80% [37]. Gene therapy targeting VEGF gene expression improved muscle capillarisation [38]. TSP-1 is a large matrix glycoprotein whose action principally serves to inhibit angiogenesis [36].…”