During embryonic heart development, the progenitor cells in the epicardium would migrate and differentiate into noncardiomyocytes in myocardium and affect the integrity of ventricular wall, but the underline mechanism has not been well studied. We have found that myocardium geranylgeranyl diphosphate synthase (Ggpps), a metabolic enzyme for cholesterol biosynthesis, is critical for cardiac cytoarchitecture remodelling during heart development. Here, we further reveal that epicardial Ggpps could also regulate ventricular wall architecture integrity. Epicardium-specific deletion of Ggpps before embryonic day 10.5 (E10.5) is embryonic lethal, while after E13.5 is survival but with defects in the epicardium and ventricular wall structure. Ggpps deficiency in the epicardium enhances the proliferation of epicardial cells and disrupts cell‒cell contact, which make epicardial cells easier to invade into ventricular wall. Thus, the fibroblast proliferation and coronary formation in myocardium were found enhanced that might disturb the coronary vasculature remodelling and ventricular wall integrity. These processes might be associated with the activation of YAP signalling, whose nuclear distribution is blocked by Ggpps deletion. In conclusion, our findings reveal a potential link between the cholesterol metabolism and heart epicardium and myocardium development in mammals, which might provide a new view of the cause for congenital heart diseases and potential therapeutic target in pathological cardiac conditions.

中文翻译：

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胆固醇代谢酶 Ggpps 调节小鼠心外膜发育和心室壁结构完整性

在胚胎心脏发育过程中，心外膜祖细胞会迁移并分化为心肌中的非心肌细胞，影响心室壁的完整性，但其机制尚未得到很好的研究。我们发现心肌香叶基香叶基二磷酸合酶 (Ggpps) 是一种用于胆固醇生物合成的代谢酶，对心脏发育过程中的心脏细胞结构重塑至关重要。在这里，我们进一步揭示心外膜 Ggpps 也可以调节心室壁结构的完整性。在胚胎第 10.5 天 (E10.5) 之前心外膜特异性缺失Ggpps是胚胎致死的，而在 E13.5 之后是存活但心外膜和心室壁结构存在缺陷。ggpps心外膜缺损会促进心外膜细胞的增殖，破坏细胞间的接触，使心外膜细胞更容易侵入心室壁。因此，发现心肌中的成纤维细胞增殖和冠状动脉形成增强，这可能会干扰冠状动脉血管重塑和心室壁完整性。这些过程可能与 YAP 信号的激活有关，其核分布被Ggpps删除所阻断。总之，我们的研究结果揭示了胆固醇代谢与哺乳动物心脏外膜和心肌发育之间的潜在联系，这可能为先天性心脏病的病因和病理性心脏病的潜在治疗靶点提供新的观点。