Alterations in retinoic acid signaling affect the development of the mouse coronary vasculature.
Alterations in retinoic acid signaling affect the development of the mouse coronary vasculature.
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DOI：
10.1002/dvdy.24639
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发表时间：
2018-08
期刊：
影响因子：
--
通讯作者：
Moise AR
中科院分区：
文献类型：
--
作者：
Wang S;Huang W;Castillo HA;Kane MA;Xavier-Neto J;Trainor PA;Moise AR
在心脏发育的最后阶段，心肌通过旁分泌因子和来自心外膜的细胞祖细胞生长并血管化。有证据表明，维甲酸（RA），维生素A的代谢产物，在心外膜为基础的发育编程中发挥重要作用。然而，在冠状动脉发展中RA信号改变的后果尚未得到系统的研究。我们探讨了在涉及心外膜的晚期心源性事件中RA信号改变的发育后果。为此，我们采用了胚胎RA过量模型的基础上缺乏的小鼠胚胎在视黄醇还原酶DHRS 3，和一个补充模型的基础上的RA合成的药理学抑制胚胎RA缺乏症。我们发现，胚胎RA信号的改变导致心肌变薄和异常冠状动脉血管形成和重塑。RA信号的过量和不足均与心室覆盖率和冠状血管密度的降低、血管形态的改变和心外膜源性壁细胞募集受损相关。使用联合转录组和蛋白质组分析方法，我们发现RA治疗心外膜细胞影响心脏发育相关的关键信号通路。心外膜RA信号传导在支持心肌生长所需的冠状动脉血管系统的发育中起关键作用。
During the final stages of heart development the myocardium grows and becomes vascularized via paracrine factors and cell progenitors derived from the epicardium. There is evidence to suggest that retinoic acid (RA), a metabolite of vitamin A, plays an important role in epicardial-based developmental programming. However, the consequences of altered RA-signaling in coronary development have not been systematically investigated. We explored the developmental consequences of altered RA-signaling in late cardiogenic events that involve the epicardium. For this, we employed a model of embryonic RA excess based on mouse embryos deficient in the retinaldehyde reductase DHRS3, and a complementary model of embryonic RA deficiency based on pharmacological inhibition of RA synthesis. We found that alterations in embryonic RA-signaling led to a thin myocardium and aberrant coronary vessel formation and remodeling. Both excess, and deficient RA-signaling are associated with reductions in ventricular coverage and density of coronary vessels, altered vessel morphology and impaired recruitment of epicardial-derived mural cells. Using a combined transcriptome and proteome profiling approach, we found that RA treatment of epicardial cells influenced key signaling pathways relevant for cardiac development. Epicardial RA-signaling plays critical roles in the development of the coronary vasculature needed to support myocardial growth.
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