Effect of short-chain fatty acids on endothelial signaling pathways in the pathogenesis of aortic aneurysm and aortic dissection

• Applicant: Dr. Thorsten Eierhoff
• Subject Area: Cardiac and Vascular Surgery
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 559907522

Impaired endothelial integrity is involved in many arterial diseases and presumably also in aortic aneurysms and dissections. VE-cadherin, a junctional adhesion and signaling protein involved in the establishment and regulation of endothelial cell-cell contacts, is considered an essential factor for vascular integrity and homeostasis. The phosphorylation of specific tyrosines of VE-cadherin in response to angiogenic and inflammatory stimuli is of fundamental importance for these processes. Short-chain fatty acids (SCFA), metabolites secreted by the gut microbiota such as butyrate, are closely associated with the occurrence and progression of vascular diseases that can affect the integrity of the endothelium. To date, it is not understood how endothelial processes are influenced by SCFA at the molecular level. In our previous studies, we identified a signaling pathway in human aortic endothelial cells that, based on the activation of the SCFA receptors FFAR2/3 by butyrate, modifies the phosphorylation state of VE-cadherin and thereby leads to an impairment of endothelial barrier function. This signaling pathway may play a role in the development and progression of aortic pathologies. The aim of the research project is to gain a deeper understanding of the aortic endothelial processes influenced by SCFA and to identify unknown relationships between gut microbiota metabolites and pathophysiological processes in the human aorta. The pathophysiological significance of the FFAR2/3-VE-cadherin signaling pathway in vitro and in situ will be further elucidated and other SCFA besides butyrate will be investigated. In addition, it will be clarified which SCFA circulate in the blood of aortic patients and which endothelial signaling pathways activate or influence them. The focus here is on processes regulated by angiotensin-II and TGF-β, which also play a role in aortic pathologies and are associated with impaired endothelial barrier function. In a further, integrative approach, metabolite-dependent signaling pathways and networks will be identified using proteomics and transcriptomics in the intima of the aorta and possible associations with the clinical pictures of aortic pathologies will be investigated. In addition to the expected gain in basic scientific knowledge, the generated data will be important for the identification and development of new (vascular surgery) treatment strategies and biomarkers based on gut microbiota metabolites.

• DFG Programme: Research Grants