Determination of the Cardiovascular Phenotype of Different Transgenic Mouse Models
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Max-Planck-Institut für Physiologische und Klinische Forschung, Kerckhoff-Institut, Abteilung Experimentelle Kardiologie in Bad Nauheim
Tag der mündlichen Prüfung:
Kurzfassung auf Englisch:
Background: Fibroblast growth factors 1 and 2 (FGF–1 and FGF–2), potent mitogens for endothelial cells and vascular smooth cells, are
implicated in arterial and capillary growth as well as in cardioprotection. Monocyte chemoattractant protein 1 (MCP–1) is involved in various
inflammatory conditions. Utilizing transgenic mice (TG) overexpressing FGF–1, FGF–2, or MCP–1 and nontransgenic controls (NTG), the
effects 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 and
reoxygenation. The releases of CK and LDH were quantified. 2. The coronary flow of the hearts of FGF–1 TG and NTG was quantified
utilizing ex vivo retrograde perfusion under maximal vasodilation at four different pressures. 3. Right femoral arteries of FGF–2 TG and NTG
were occluded. Mice were assigned to a sedentary or a trained group. After 5 weeks, collateral dependent blood flows to the foot and to the
gastrocnemius muscle were determined. Exercise capacity was accessed, postmortem angiograms and histomorphometry of collateral
arteries were performed. 4. Exercise tolerance of MCP–1 TG and NTG was determined by graded exercise tests over a period of four
months. 5. The relationship between recovery of exercise capacity and increase in collateral dependent blood flow after bilateral femoral
artery 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 dependent
increase in coronary flow was markedly elevated in hearts of FGF–1 TG. 3. Foot and gastrocnemius blood flows as well as exercise
capacity were increased in trained FGF–2 TG that showed the formation of a dense collateral network. 4. Exercise tolerance of MCP–1 TG
was 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 coronary
flow. General FGF–2 overexpression and training enhance the formation of a dense collateral network, increase collateral dependent blood
flow and exercise capacity. Cardiacspecific MCP–1 overexpression induces myocarditis and causes exercise intolerance as a typical
symptom of congestive heart failure. Recovery of collateral dependent resting blood flow partially increases exercise capacity.