Embryonic mechanisms of coronary precursor differentiation: principles for cell therapy.

Author(s)

Ana Paula Azambujá

• Document type: Doctoral Thesis
• Press: São Paulo.
• Institution: Universidade de São Paulo (USP). Instituto de Ciências Biomédicas (ICB/SDI)
• Defense date: 2009-08-17

Examining board members

José Xavier Neto; Francisco Rafael Martins Laurindo; Ayumi Aurea Miyakawa; Marinilce Fagundes dos Santos; Deborah Schechtman

• Advisor: José Xavier Neto

Abstract

Coronary vessels derive from the proepicardium (PE), a structure formed by precursor of coronary vessels cells, endothelial and smooth muscle cells (CoSMC). In vivo there is a clear gap between the endothelial differentiation and the integration of CoSMC into the vascular tubes. The aim of this work was to understand the mechanisms controlling the delayed in vivo CoSMC differentiation. Based on the progressive loss of expression of raldh2, the main retinoic acid (RA) synthesizing enzyme, we explored the RA signaling as a possible candidate inhibitor of CoSMC differentiation. Using a adenoviral raldh2 expression system and in vivo inhibition of RA synthesis we showed that RA signaling act as a brake to slow CoSMC differentiation in PE-derived cells. We also identified VEGF as key factor acting on the control of CoSMC differentiation. Together our results support a model that AR and VEGF synthesis during cardiac development was co-opted to block the CoSMC differentiation of coronary precursors before an extensive endothelial network of tubes is established. (AU)