Exploring the role of PRDM16 in arterial development and disease

• Applicant: Manu Beerens, Ph.D.
• Subject Area: Cardiology, Angiology ; General Genetics and Functional Genome Biology ; Public Health, Healthcare Research, Social and Occupational Medicine ; Cell Biology
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 545459527

The transcription factor Positive Regulatory Domain containing protein 16 (PRDM16) plays a critical role in brown adipose and neuronal development and is vital for the maintenance and homeostasis of diverse stem cell populations in multiple organs. Genome-wide association studies have linked pathogenic variants in the coding region of PRDM16 to early-onset heart failure, consistent with its ventricular restricted expression pattern in the heart and recent evidence in zebrafish and mice indicating a crucial role for PRDM16 in cardiac development and function. The presence of PRDM16 within the cardiovascular system is however not confined to ventricular cardiomyocytes, as we and others have documented abundant PRDM16 protein levels in arterial but not venous endothelial cells during development and throughout adulthood. We further showed that endothelial-specific Prdm16 knockout mice display ischemia-induced endothelial dysfunction, collateral artery deficiency, and reduced perfusion recovery after femoral artery ligation. We additionally demonstrated that Prdm16 interacts with canonical Notch signaling during vascular development in zebrafish via mechanisms incompletely understood. Despite these findings, the function of endothelial PRDM16 in arterial development and disease remains unclear. As recent studies highlighted a potential role for PRDM16 in coronary artery disease and stroke, a better understanding of the precise role of PRDM16 – and by extension its paralog PRDM3 – in endothelial and arterial development and homeostasis in health and disease is urgently needed. Therefore, this multidisciplinary proposal aims to further characterize the molecular mechanisms downstream endothelial PRDM3/16-mediated signaling in vascular development and study its role in arterial thrombosis using radical-driven EC injury (FeCl3-induced stasis in femoral artery) and stasis-driven thrombosis (ligation of carotid artery) mouse models and human disease-relevant in vitro approaches.

• DFG Programme: Research Grants