Abstract 750: Capillary Remodeling and Angiogenesis in Cardiac Hypoxia Inducible Factor 1-alpha Over Expression
Hypoxia inducible factor-1 (HIF-1) is a heterodimeric, oxygen sensitive transcription factor that coordinates the response to hypoxia in all mammals, regulating a large number genes involved in processes including angiogenesis and glycolytic metabolism. A mutated form of the HIF-1α component was created for these studies, resistant to the usual oxygen-related degradation of the endogenous protein. A transgenic mouse line was developed in which expression of this stabilized HIF-1α construct was controlled by a tetracycline-responsive promoter. HIF-1α expression was induced for 7 days in adult mouse heart, resulting in angiogenesis and ventricular dysfunction. Gross physiological inspection demonstrated large epicardial vessels with prominent side branches. Histological analysis revealed that these vessels had the typical organization of veins, with thin walls and minimal medial and serosal layers. The myocardium showed hypertrophy and heterogeneity of myocyte size, drop out of myofibers, and mildly increased interstitial fibrosis. Lectin staining of heart sections after 7 days of HIF-1α over expression yielded an approximately 50% increase in capillary density (p=0.003). Corrosion casts were made by perfusing two day HIF-1α over expression hearts with a new low-viscosity resin, PU4ii (VasQtec, Switzerland). Following curing, heart tissue was macerated and casts were decalcified, lyophilized, coated with colloidal gold and subject to scanning electron microscopy. The images taken qualitatively illustrate “lakes” of capillaries forming off of larger vessels, but time course experiments need to be completed to fully demonstrate the mechanism of the capillary increase. This study establishes the potential for HIF-1 to increase capillary density in adult heart tissue, setting the stage for HIF-1 gene therapy to enhance perfusion and treat ischemia.