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Effects of vascular endothelial growth factor (VEGF)A and VEGFB gene transfer on vascular reserve in a conscious rabbit hindlimb ischaemia model

Authors


  • Presented at the 35th Annual Scientific Meeting of the Australasian Society of Clinical and Experimental Pharmacologists and Toxicologists, Dunedin, New Zealand, 3–5 December 2001.

Dr Christine E Wright, Department of Pharmacology, University of Melbourne, Victoria 3010, Australia. Email: cewright@unimelb.edu.au

Summary

1. As a result of the ageing population, there are increasing numbers of patients with severe peripheral vascular occlusive disease associated with intermittent claudication (pain on walking) and decreased exercise tolerance. There is a great clinical need for pharmacological treatments that may stimulate collateral blood vessel growth, increase vascularity and improve skeletal muscle function.

2. Therapeutic angiogenesis using growth factors such as vascular endothelial growth factor (VEGF) has been used to improve collateral artery development in myocardial or skeletal muscle ischaemia. The broad aims of the work briefly summarized here were to compare the effects of VEGFA165 and VEGFB167 (500 µg, i.m., gene transfer) on calf blood pressure ratio and reactive hyperaemia in a chronic rabbit preparation with unilateral limb ischaemia.

3. Unilateral femoral artery ligation caused an immediate deficit (compared with the contralateral limb) of 72% in calf systolic blood pressure. There were improvements 14 days after ligation with VEGFA and VEGFB treatments compared with the vehicle control plasmid treatment, but a deficit remained of some 32%.

4. Reactive hyperaemic responses were significantly attenuated 7 days after ligation in the vehicle and VEGFA treatment groups. On day 14, this loss of vascular reserve was restored in the VEGFA group, but remained in the vehicle group (−30%). In VEGFB-treated animals, there was no deficit in reserve 7–14 days post-ligation.

5. In conclusion, there is considerable value in the serial measurements of calf blood pressure ratio and reactive hyperaemia in the rabbit unilateral hindlimb ischaemia model. Gene transfer of either VEGFA or VEGFB allowed significant improvements in these indices compared with vehicle but, at 14 days post-ligation, large deficits still remained. Studies extending this experimental period are in progress.

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