The role of RNA-binding proteins in cardiac endothelial cell function and angiogenesis

• Applicant: Dr. Sandhya Singh, Ph.D.
• Subject Area: Cardiology, Angiology ; Cell Biology
• Term: since 2026
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 574136796

Cardiac endothelial cells (ECs) are highly heterogeneous and essential for maintaining heart function by regulating oxygen/nutrient delivery and responding to physiological and pathological stimuli. In heart disease, ECs contribute significantly to fibrosis and remodeling, in part through endothelial-to-mesenchymal transition and paracrine signaling. RNA-binding proteins (RBPs) play pivotal roles in post-transcriptional gene regulation by influencing splicing, RNA stability, and translation. Despite their importance, the post-transcriptional roles of RBPs in cardiac EC function remain underexplored. Recent work from the host lab demonstrated that TGF-β stimulation leads to global changes in RNA-protein interactions in cardiac ECs, implicating RBPs in mesenchymal activation. Similarly, angiogenesis is a key process in cardiac repair post-injury, which is primarily led by ECs in response to VEGF-A. Although VEGF-A has been considered for therapeutic angiogenesis, its clinical use is limited by short half-life and off-target effects, suggesting a need for more refined strategies. Preliminary studies in the host lab explored VEGF-A’s effect on RNA interactome in mouse cardiac ECs (MCECs), identifying dynamic changes in RBP binding. Rbfox2, a key RBP involved in RNA splicing and stability, was found to be acutely downregulated in RNA binding activity upon VEGF-A stimulation, both in MCECs and primary human ECs (HUVECs). This reduction correlated with nuclear export and was found to be mediated via the AKT pathway. Functionally, Rbfox2 knockdown enhanced angiogenesis, confirmed with the sprouting, tubule formation, and proliferation assays in HUVECs, suggesting that VEGF-A-mediated inhibition of Rbfox2 may promote angiogenesis. RNA immunoprecipitation and sequencing identified significant shifts in Rbfox2 target interactions after VEGF-A exposure, particularly with RNAs involved in vascular development and morphogenesis. This project aims to define the mechanistic role of Rbfox2 in VEGF-A-driven angiogenesis by examining how VEGF-A alters Rbfox2-RNA interactions, potentially via post-translational modifications. The study will also explore how loss of Rbfox2 impacts angiogenic signaling and EC behavior. Ultimately, identifying specific Rbfox2 target RNAs may offer novel therapeutic opportunities to enhance angiogenesis in ischemic heart conditions, such as myocardial infarction, via targeted post-transcriptional regulation.

• DFG Programme: Position