Cell- and organotypic functions of SRF and its cofactor ELK3 in the lymphatic system

• Applicant: Dr. Michael Orlich
• Subject Area: Cell Biology
• Term: since 2026
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 572113215

The lymphatic vasculature is essential for interstitial fluid uptake and return to the venous circulation. This process depends on specialized lymphatic endothelial cells (LECs) that permit fluid entry at capillaries while maintaining tight junctions in collecting vessels, where lymph transport is driven by contractions of lymphatic muscle cells (LMCs). Dysfunction in either LECs or LMCs results in lymphedema, affecting up to 250 million people globally. SRF and its cofactor ELK3 are ubiquitously expressed transcription factors that regulate contractile and immediate early gene expression. I previously demonstrated that Srf deletion in vascular smooth muscle cells abolishes contractile function, resulting in arteriovenous shunt formation. Although SRF plays a critical role in smooth muscle biology and LMC contractility declines with age, the SRF pathway has not been systematically studied in LMCs. Similarly, constitutive Elk3 knockout (Elk3-KO) causes postnatal lethality due to impaired chyle uptake in pleural lymphatics (chylothorax), but this phenotype remains poorly characterized, and the roles of ELK3 and SRF in the lymphatic vasculature are largely unexplored. Our preliminary data from Elk3-KO mice revealed pronounced lymphatic vessel hyperplasia in the diaphragm, whereas ear skin lymphatics were only mildly affected. This suggests a specific role for ELK3 in LECs exposed to greater mechanical stress. Supporting this, ELK3 expression in human dermal LECs decreases in response to increased substrate stiffness in vitro. Additionally, ELK3 knockdown experiments revealed disrupted cell junctions and enhanced F-actin stress fiber formation, identifying ELK3 as a potential novel mechanosensitive regulator of lymphatic endothelial function. Further preliminary data show that Srf expression in LMCs declines with age, correlating with reduced expression of key contractile proteins. Conditional Srf deletion in LMCs lead to loss of these proteins and pronounced dilation of collecting lymphatic vessels, supporting the hypothesis that SRF is an age-regulated factor essential for LMC contractility. Building on these findings, we will employ constitutive and LEC-specific Elk3 knockout animal models to investigate its mechanistic role in embryonic and postnatal lymphatic development and in adult lymphatic homeostasis. Similarly, we will explore if age-related loss of SRF in LMCs impairs lymphatic function and contributes to lymphedema. Overall, this study seeks to identify ELK3 as a novel regulator of LEC junctional integrity and to establish SRF as a key factor in lymphatic aging, with potential therapeutic relevance for combating lymphatic dysfunction and lymphedema.

• DFG Programme: Research Grants