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Azambuja AP. Embryonic mechanisms of coronary precursor differentiation: principles for cell therapy [Ph.D. Thesis]. São Paulo: Instituto de Ciências Biomédicas da Universidade de São Paulo; 2009. Coronary vessels derive from the proepicardium, a transient embryonic structure formed by precursor cells of the epicardium, and the constituents coronary vessels such as endothelial and smooth muscle cells (CoSMC). In vivo there is a clear gap between the endothelial differentiation and the integration of differentiated CoSMC into the endothelial tubes. The mechanisms underlying the delayed in vivo CoSMC differentiation have not been addressed. Based on the progressive loss of expression of raldh2, the main retinoic acid (RA) synthesizing enzyme during coronary precursor differentiation, we explored the RA signaling as a possible candidate inhibitor of precocious CoSMC differentiation. Using a nonreplicative adenoviral raldh2 expression system and in vivo inhibition of RA synthesis we showed that RA signaling act as a brake to slow coronary smooth muscle 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.

Mecanismos embrionários de diferenciação de precursores coronários: princípios para aplicação em terapia celular.