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Doctoral Thesis
DOI
10.11606/T.42.2009.tde-09112009-144701
Document
Author
Full name
Ana Paula Azambujá
Institute/School/College
Knowledge Area
Date of Defense
Published
São Paulo, 2009
Supervisor
Committee
Xavier Neto, José (President)
Laurindo, Francisco Rafael Martins
Miyakawa, Ayumi Aurea
Santos, Marinilce Fagundes dos
Schechtman, Deborah
Title in Portuguese
Mecanismos embrionários de diferenciação de precursores coronários: princípios para aplicação em terapia celular.
Keywords in Portuguese
Ácido retinóico
Coronárias
Desenvolvimento cardíaco
Embriologia molecular
Endotélio
Histologia
Músculo liso vascular
Terapia celular
Abstract in Portuguese
As coronárias derivam do proepicárdio, uma estrutura formada por precursores dos constituintes de vasos coronários, células endoteliais e musculares lisas (CoSMC). In vivo observa-se um marcante atraso entre a diferenciação endotelial e a integração de CoSMC à parede do vaso. O objetivo deste trabalho foi identificar os mecanismos que inibem a diferenciação a CoSMC in vivo. Baseados na perda progressiva da expressão de raldh2, a principal enzima de síntese de ácido retinóico (AR), nós exploramos a sinalização por AR como um possível inibidor da diferenciação a CoSMC. Através de um vetor adenoviral de expressão de raldh2 e da inibição in vivo da síntese de AR nós demonstramos que a sinalização por AR bloqueia a diferenciação a CoSMC dos precursores coronários. Nós também identificamos o VEGF como um fator chave no controle da diferenciação a CoSMC. Em conjunto, nossos dados suportam o modelo que a síntese de AR e VEGF durante o desenvolvimento cardíaco foi co-optada para o bloqueio da diferenciação a CoSMC até o estabelecimento de uma vasta malha vascular.
Title in English
Embryonic mechanisms of coronary precursor differentiation: principles for cell therapy.
Keywords in English
Cell therapy
Coronary
Endothelium
Heart development
Histology
Molecular embryology
Retinoic acid
Vascular smooth muscle
Abstract in English
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.
 
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Publishing Date
2010-02-03
 
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