Heart failure due to high blood pressure or ischemic injury remains a major problem for millions of patients worldwide. Despite enormous advances in deciphering the molecular mechanisms underlying heart failure progression, the cell-type specific adaptations and especially intercellular signaling remain poorly understood. Cardiac fibroblasts express high levels of cardiogenic transcription factors such as GATA-4 and GATA-6, but their role in fibroblasts during stress is not known. Here, we show that fibroblast GATA-4 and GATA-6 promote adaptive remodeling in pressure overload induced cardiac hypertrophy. Using a mouse model with specific single or double deletion of Gata4 and Gata6 in stress activated fibroblasts, we found a reduced myocardial capillarization in mice with Gata4/6 double deletion following pressure overload, while single deletion of Gata4 or Gata6 had no effect. Importantly, we confirmed the reduced angiogenic response using an in vitro co-culture system with Gata4/6 deleted cardiac fibroblasts and endothelial cells. A comprehensive RNA-sequencing analysis revealed an upregulation of anti-angiogenic genes upon Gata4/6 deletion in fibroblasts, and siRNA mediated downregulation of these genes restored endothelial cell growth. In conclusion, we identified a novel role for the cardiogenic transcription factors GATA-4 and GATA-6 in heart fibroblasts, where both proteins act in concert to promote myocardial capillarization and heart function by directing intercellular crosstalk.

高血压或缺血性损伤引起的心力衰竭仍然是全世界数百万患者的主要问题。尽管在破译心力衰竭进展的分子机制方面取得了巨大进展，但细胞类型特异性适应，尤其是细胞间信号传导仍然知之甚少。心脏成纤维细胞表达高水平的心源性转录因子，例如 GATA-4 和 GATA-6，但它们在应激期间在成纤维细胞中的作用尚不清楚。在这里，我们发现成纤维细胞 GATA-4 和 GATA-6 促进压力超负荷引起的心脏肥大的适应性重塑。使用在应激激活的成纤维细胞中特异性单次或双次删除Gata4和Gata6 的小鼠模型，我们发现Gata4/6双删除的小鼠在压力超负荷后心肌毛细血管化减少，而单次删除Gata4或Gata6则没有效果。重要的是，我们使用Gata4/6缺失的心脏成纤维细胞和内皮细胞的体外共培养系统证实了血管生成反应的减少。全面的 RNA 测序分析显示，成纤维细胞中Gata4/6缺失后抗血管生成基因上调，而 siRNA 介导的这些基因下调可恢复内皮细胞生长。总之，我们确定了心源性转录因子 GATA-4 和 GATA-6 在心脏成纤维细胞中的新作用，这两种蛋白协同作用，通过指导细胞间串扰来促进心肌毛细血管化和心脏功能。