Background: Fibroblast growth factors 1 and 2 (FGF 1 and FGF 2), potent mitogens for endothelial cells and vascular smooth cells, areimplicated in arterial and capillary growth as well as in cardioprotection. Monocyte chemoattractant protein 1 (MCP 1) is involved in variousinflammatory conditions. Utilizing transgenic mice (TG) overexpressing FGF 1, FGF 2, or MCP 1 and nontransgenic controls (NTG), theeffects of these factors on vascular development, cellular protection, cardiac performance, and exercise tolerance were studied.
Methods: 1. Ventricular cardiac myocytes of hearts of FGF 1 TG and NTG were isolated and submitted to simulated ischemia andreoxygenation. The releases of CK and LDH were quantified. 2. The coronary flow of the hearts of FGF 1 TG and NTG was quantifiedutilizing ex vivo retrograde perfusion under maximal vasodilation at four different pressures. 3. Right femoral arteries of FGF 2 TG and NTGwere occluded. Mice were assigned to a sedentary or a trained group. After 5 weeks, collateral dependent blood flows to the foot and to thegastrocnemius muscle were determined. Exercise capacity was accessed, postmortem angiograms and histomorphometry of collateralarteries were performed. 4. Exercise tolerance of MCP 1 TG and NTG was determined by graded exercise tests over a period of fourmonths. 5. The relationship between recovery of exercise capacity and increase in collateral dependent blood flow after bilateral femoralartery occlusion was investigated in three different mouse strains.
Results: 1. CK and LDH release of myocytes of FGF 1 TG was reduced at 4h and 8h of simulated ischemia. 2. The pressure dependentincrease in coronary flow was markedly elevated in hearts of FGF 1 TG. 3. Foot and gastrocnemius blood flows as well as exercisecapacity were increased in trained FGF 2 TG that showed the formation of a dense collateral network. 4. Exercise tolerance of MCP 1 TGwas markedly reduced. 5. Increased collateral dependent foot blood flow is only partially reflected by the recovery of exercise capacity.
Conclusions: Cardiac-specific FGF 1 overexpression protects ventricular myocytes against simulated ischemia and increases coronaryflow. General FGF 2 overexpression and training enhance the formation of a dense collateral network, increase collateral dependent bloodflow and exercise capacity. Cardiacspecific MCP 1 overexpression induces myocarditis and causes exercise intolerance as a typicalsymptom of congestive heart failure. Recovery of collateral dependent resting blood flow partially increases exercise capacity.
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