Impaired biophysical cues alter vascular integrity in cardiolaminopathy

Cardiolaminopathy is a severe myocardial disease caused by pathogenic variants in the LMNA gene, leading to left ventricular dysfunction and contributing to heart failure and the need for transplantation. While nuclear abnormalities in cardiac stromal cells are well documented, the impact of vascular involvement remains underexplored. Since LMNA is also expressed in vascular smooth muscle cells (VSMCs), its dysfunction may induce vascular abnormalities, exacerbating disease progression. To investigate this, semi-automated digital quantification of cardiac vessels was performed on human explanted hearts with end-stage cardiolaminopathy (variants: Q103R, E317K, R331Q, R377L) and compared to three non-remodeled controls. Three LMNA cardiolaminopathy variants (R331Q, R349E, R377L) were subsequently modeled using human induced pluripotent stem cell-derived VSMCs (hiPSC-VSMCs) under 2D and 3D conditions to evaluate vascular integrity through calcification assays, nanoindentation, and immunocytochemistry. These findings suggest that LMNA-mutated iVSMCs undergo structural and mechanical alterations that disrupt vascular homeostasis, affecting cytoskeletal dynamics, nuclear stability, and mineralization propensity. The impact of LMNA dysfunction extends beyond cellular architecture, influencing mechanical properties such as stiffness and elasticity, essential for vascular resilience. These observations highlight the crucial role of vascular remodeling in cardiolaminopathy, offering new perspectives on its progression and potential therapeutic targets.