Retinoic Acid and VEGF Delay Smooth Muscle Relative to Endothelial Differentiation to Coordinate Inner and Outer Coronary Vessel Wall Morphogenesis

Autor(es)

Azambuja, Ana P. ^{[1, 2]} ; Portillo-Sanchez, Victor ^[3] ; Rodrigues, Mariliza V. ^[1] ; Omae, Samantha V. ^[1] ; Schechtman, Deborah ^[4] ; Strauss, Bryan E. ^[1] ; Costanzi-Strauss, Eugenia ^[2] ; Krieger, Jose E. ^[1] ; Perez-Pomares, Jose M. ^[3] ; Xavier-Neto, Jose ^[1]

Afiliação do(s) autor(es)

^[1] Univ Sao Paulo, Lab Genet & Mol Cardiol, Inst Heart, BR-05508 Sao Paulo - Brazil

^[2] Univ Sao Paulo, Dept Dev & Cell Biol, BR-05508 Sao Paulo - Brazil

^[3] Univ Malaga, Dept Anim Biol, E-29071 Malaga - Spain

^[4] Univ Sao Paulo, Inst Chem, Dept Biochem, BR-05508 Sao Paulo - Brazil

• Tipo de documento: Artigo Científico
• Fonte: Circulation Research; v. 107, n. 2, p. 204-U87, JUL 23 2010.
• Citações Web of Science: 32

Resumo

Rationale: Major coronary vessels derive from the proepicardium, the cellular progenitor of the epicardium, coronary endothelium, and coronary smooth muscle cells (CoSMCs). CoSMCs are delayed in their differentiation relative to coronary endothelial cells (CoEs), such that CoSMCs mature only after CoEs have assembled into tubes. The mechanisms underlying this sequential CoE/CoSMC differentiation are unknown. Retinoic acid (RA) is crucial for vascular development and the main RA-synthesizing enzyme is progressively lost from epicardially derived cells as they differentiate into blood vessel types. In parallel, myocardial vascular endothelial growth factor (VEGF) expression also decreases along coronary vessel muscularization. Objective: We hypothesized that RA and VEGF act coordinately as physiological brakes to CoSMC differentiation. Methods and Results: In vitro assays (proepicardial cultures, cocultures, and RALDH2 {[}retinaldehyde dehydrogenase-2]/VEGF adenoviral overexpression) and in vivo inhibition of RA synthesis show that RA and VEGF act as repressors of CoSMC differentiation, whereas VEGF biases epicardially derived cell differentiation toward the endothelial phenotype. Conclusion: Experiments support a model in which early high levels of RA and VEGF prevent CoSMC differentiation from epicardially derived cells before RA and VEGF levels decline as an extensive endothelial network is established. We suggest this physiological delay guarantees the formation of a complex, hierarchical, tree of coronary vessels. (Circ Res. 2010;107:204-216.) (AU)

• Processo FAPESP: 06/50843-0 - Evolução e desenvolvimento das câmaras cardíacas
• Beneficiário: José Xavier Neto
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 05/60637-6 - Mecanismos embrionários de diferenciação de precursores coronários: princípios para aplicação em terapia celular
• Beneficiário: Ana Paula Azambuja
• Modalidade de apoio: Bolsas no Brasil - Doutorado