Dittrich, Gesine M.Froese, NataliWang, XueKroeger, HannahWang, HonghuiSzaroszyk, MalgorzataMalek‑Mohammadi, MonaCordero, JulioKeles, MerveKorf‑Klingebiel, MortimerWollert, Kai C.Geffers, RobertMayr, ManuelConway, Simon J.Dobreva, GerganaBauersachs, JohannHeineke, Joerg2022-09-262022-09-262021-04-19Dittrich GM, Froese N, Wang X, et al. Fibroblast GATA-4 and GATA-6 promote myocardial adaptation to pressure overload by enhancing cardiac angiogenesis. Basic Res Cardiol. 2021;116(1):26. Published 2021 Apr 19. doi:10.1007/s00395-021-00862-yhttps://hdl.handle.net/1805/30107Heart 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.en-USAttribution 4.0 InternationalCardiac remodelingFibroblastAngiogenesisIntercellular crosstalkArticle