Abstract 18147: Angiopoietin-1 is Essential for Coronary Vein Formation in the Developing Heart
Background and Aim: Ischemic heart disease is the leading cause of mortality all over the world. Elucidating the developmental program of coronary vessels would help to understand the disease and lead to its therapies. We previously reported that the signaling circuit between endothelium and myocardium mediated by neuregulin-1 and angiopoietin-1 (Ang1) contributes to cardiac homeostasis (Nakaoka et al. JCI 2007). Thus, we created cardiomyocyte-specific Ang1 knockout (Ang1CKO) mice to reveal the role of Ang1 derived from myocardium.
Methods and Results: We created Ang1CKO mice through crossing Ang1flox mice with a-MHC-Cre-transgenic mice. Ang1CKO mice displayed embryonic lethality between E12.5 and E14.5 with impaired adhesion between endocardium and myocardium, poor trabeculation and thin compact layer. In addition, CD31-immunostaining revealed that Ang1CKO embryos have severe defects in the formation of superficial coronary vessels which recapitulate the venous lineages. Expression levels of venous marker genes such as Eph receptor B4 (Ephb4) and chicken ovalbumin upstream promoter-transcription factor II(COUP-TFII) in the hearts of Ang1CKO embryos were significantly decreased compared with those of control littermates. Consistently, superficial coronary veins positive for EphB4 were not deteceted in the hearts of Ang1CKO mice, but not in those of control littermates. However the formation of coronary arteries in the heart was almost comparable between control and Ang1CKO mice. These findings suggest that Ang1 secreted from myocardium is critical for the formation of coronary veins, but not for that of coronary arteries. To reveal the involvement of Ang1 in the differentiation of premature endothelial cells, we examined the effect of cartilage oligomeric matrix protein (COMP)-Ang1, a potent variant of Ang1, on the arterial lineage recapitulation by the treatment with VEGF and cAMP in Flk1-positive embryonic stem (ES) cells. Surprisingly, co-application of Ang1 inhibited the induction of the arterial marker EphrinB2 after treatment with VEGF and cAMP, and upregulated COUP-TFII expression.
Conclusion: Collectively, Ang1 secreted from myocardium is critical for coronary vein formation in the developing heart.
- © 2012 by American Heart Association, Inc.