Abstract 21501: Ets-1 is Required for Vasculogenesis in the Developing Myocardium
Introduction: The Ets family of transcription factors are involved in a broad spectrum of biological processes including cell growth, differentiation, and lineage specification.
Results: Ets-1 null mice exhibit a near uniform lethality between day 0 and 3 after birth. We have recently reported on the role of Ets-1 in the migration and differentiation of the cardiac neural crest. Consistent with this role, histological examination revealed a membranous ventricular septal defect with severe right ventricular dilatation by echocardiography. We also observed left ventricular systolic dysfunction as measured by a decrease in fractional shortening (45.3% vs. 22.5%, p<0.0001). Although these hearts showed relatively normal wall thickness, capillary density within the myocardium was reduced by 36% in the Ets-1 null mice. Flk-1, a marker of endothelial cells was down-regulated approximately 50% in newborn Ets-1 null hearts by western analysis. To examine earlier steps in coronary vasculogenesis, we performed whole-mount PCAM staining of Ets-1 null embryonic hearts to visualize the coronary vasculature. We found significant attenuation in the formation of the coronary plexus, suggesting a defect in differentiation of coronary vascular precursor cells from the epicardium. This appears cardiac specific as capillary density in non-heart tissue beds did not differ. Expression of the epicardial markers Tbx18, Raldh, and WT1 were all normal. Further, in-situ hybridization demonstrated that at this time in embryogenesis, Ets-1 is highly expressed in the epicardium, suggesting a role for Ets-1 in coronary precursor specification. To examine this more carefully, we performed in-situ hybridization at embryonic day 14.5 with the markers Flk-1 and endoglin. Along the epicardial surface, there was no expression of these markers in Ets-1 null mice, suggesting a loss of vascular precursors within the epicardium. Finally, we show that Ets-1 synergistically activates the Flk-1 promoter in combination with GATA4, thus providing a molecular mechanism for the loss of these epicardial vascular precursors.
Conclusion: Taken together, these findings indicate that Ets-1 is required for proper vasculogenesis in the developing myocardium.
- © 2010 by American Heart Association, Inc.