Absence of GDF15 Aggravates Pressure Overload-Induced Cardiac Remodelling in Mice Hallmarked by Perivascular Fibrosis and Signs of Endothelial-to-Mesenchymal Transition

Growth differentiation factor 15 (GDF15) levels are associated with increased mortality and rehospitalisation in heart failure (HF) patients. Whether GDF15 is causally involved in the pathobiology of HF remains largely unknown. Using the transverse aortic constriction (TAC) mouse model, we investigated the role of GDF15 in pressure overload-induced HF. Following TAC, circulating GDF15 levels increased significantly. Compared to wild type (WT) littermates, genetically deficient Gdf15^-/- mice developed more pronounced adverse cardiac remodelling one week after TAC, characterised by increased cardiac volumes and impaired myocardial global deformation. This further aggravated into severe HF in Gdf15^-/- mice over 42 days follow-up. Cardiac remodelling in Gdf15^-/- was accompanied by enhanced perivascular fibrosis and increased co-localization of fibroblast- and endothelial-specific markers in the cardiac endothelium of Gdf15^-/- mice, suggestive of endothelial plasticity and Endothelial-to-Mesenchymal transition (EndMT)-like changes. To further explore potential endothelial mechanisms underlying these observations, we performed complementary in vitro experiments in GDF15 knockdown endothelial cells. GDF15 deficiency impaired barrier function and enhanced Activin A-induced mesenchymal marker expression, consistent with increased endothelial phenotypic modulation. Together, these findings demonstrate that the loss of GDF15 aggravates pressure overload-induced heart failure, hallmarked by perivascular fibrosis and signs of endothelial dysfunction. Our data further support a potential protective role for GDF15 in maintaining endothelial integrity during cardiac stress.