THE DEVELOPMENT AND ENHANCEMENT OF THE COLLATERAL CIRCULATION IN AN ANIMAL-MODEL OF LOWER-LIMB ISCHEMIA

In an animal model of hind limb ischaemia we documented the levels of endogenous basic fibroblast growth factor (bFGF) in control and ischaemic hind limbs, and evaluated the response to the administration of exogenous recombinant bFGF and heparin. Variations in this model were tested for their ability to alter the development of the collateral circulation. Recovery after acute arterial occlusion was significantly delayed by immediate bilateral mirror-image arterial ligations, when compared with either unilateral arterial ligation or delayed contralateral ligations performed after 2 months. If the major veins were also occluded all limbs developed gangrene, tissue loss and a marked delay in the recovery of blood flow, while none of the animals with unilateral arterial ligations developed gangrene. This indicates that the recovery in blood flow during the acute phase in this model is dependent on collateral vessels from the contralateral iliac artery and that major venous occlusion impedes the development of collateral vessels. Lumbar sympathectomy did not alter the recovery of blood flow after arterial occlusion, suggesting that collateral blood flow is not significantly influenced by autonomic neural supply. Following arterial occlusion there was a ten-fold increase in the levels of endogenous bFGF in all ischaemic muscle groups. Intramuscular implantation of bFGF in heparin-sepharose pellets at the time of arterial ligation markedly enhanced the blood flow for 3 weeks compared with untreated ischaemic limbs. A further increment in blood flow occurred if an additional dose of bFGF was administered 4 weeks after ligation. Administration of heparin for 1 week during either the acute or chronic phases of collateral development significantly improved the blood flow in ischaemic limbs. This was neither as profound nor as prolonged as that observed for bFGF. Treatment with heparin for 4 weeks following arterial ligation provide an increased blood flow for the first 3 weeks. These results indicate that tissues respond to ischaemia by an increased release of bFGF and that the evolution of collateral vessels can be enhanced by the administration of both exogenous recombinant bFGF and heparin. We conclude that bFGF is an important biochemical mediator in the development of the collateral circulation.