Mutational studies in genetically engineered mice have shown that the angiopoietin/Tie2(Tek) signaling pathway is indispensable for vascular development. To further investigate the role of Angiopoietin 1 in heart development, we developed transgenic mice that express Angiopoietin 1 under control of doxycycline in cardiac myocytes. Ninety percent of all transgenic mice die between embryonic day 12.5 and 15.5. Beginning at embryonic day 12.5, transgenic mice exhibit dilated atria, a significant thinning of the myocardial wall, and eventual outflow tract collapse. In addition, hearts of the most severely affected transgenic embryos have no coronary arteries as a result of the defective development and maintenance of the epicardium. The subsequent lack of blood and nutrient delivery to the developing heart may account for decreases in N-cadherin expression and subsequent loss of cell-cell contact leading to cell death, and ultimately the collapse and hemorrhage of the heart. These results suggest a pivotal role for Angiopoietin 1 in cardiovascular development, specifically the development of the epicardium and coronary vasculature.
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