Angiopoietin 1 expression levels in the myocardium direct coronary vessel development.
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.
Division of Molecular and Cellular Biology Research, Sunnybrook and Women's College Research Institute, Toronto, Ontario, Canada.
Nicole L
NL
Ward
Paul
P
Van Slyke
Celina
C
Sturk
Maribelle
M
Cruz
Daniel J
DJ
Dumont
D042683:Angiopoietin-1 / Q000096:biosynthesis* / Q000378:metabolism / Q000502:physiology; D000818:Animals; D015153:Blotting, Western; D015820:Cadherins / Q000378:metabolism; D003331:Coronary Vessels / Q000196:embryology* / Q000473:pathology*; D015509:Developmental Biology / Q000379:methods*; D004318:Doxycycline / Q000494:pharmacology; D018507:Gene Expression Regulation, Developmental; D005838:Genotype; D006321:Heart / Q000196:embryology*; D006470:Hemorrhage; D007150:Immunohistochemistry; D051379:Mice; D008822:Mice, Transgenic; D008957:Models, Genetic; D009206:Myocardium / Q000473:pathology*; D010496:Pericardium / Q000378:metabolism; D011233:Precipitin Tests; D015398:Signal Transduction; D013997:Time Factors
D042683:Angiopoietin-1; D015820:Cadherins; D004318:Doxycycline