Cell-specific ERK2 signaling in vascular smooth muscle cells drives vascular dysfunction and systolic heart failure

Extracellular signal-regulated kinases 1 and 2 (ERK1/2) are central regulators of cardiovascular development and stress responses and have been implicated in the cardiovascular toxicity of tyrosine kinase inhibitors. While ERK signaling in cardiomyocytes has been extensively investigated, the isoform- and cell-specific contribution of ERK2 in vascular smooth muscle cells (VSMCs) to cardiac dysfunction remains incompletely understood. To address this issue, we generated mice with systemic deletion of Erk1 (Erk1^-/-), SM22α-Cre-mediated deletion of Erk2 (SM22α-E2KO; targeting VSMCs and cardiomyocytes), and α-myosin heavy chain-Cre-mediated deletion of Erk2 in cardiomyocytes alone (MHCα-E2KO). SM22α-E2KO mice developed progressive eccentric left ventricular hypertrophy, systolic dysfunction, impaired exercise capacity, and markedly reduced survival, whereas MHCα-E2KO and Erk1^-/- mice exhibited preserved cardiac structure and function under basal conditions. Vascular functional studies revealed enhanced phenylephrine-induced vasoconstriction and impaired acetylcholine-mediated relaxation in SM22α-E2KO mice, despite preserved ERK2 expression in aortic endothelial cells. Aortic RhoA/Rho-kinase activity was significantly increased in SM22α-E2KO mice, and pharmacological inhibition of Rho-kinase normalized vascular hypercontractility. Transcriptomic analyses of the heart demonstrated downregulation of excitation-contraction coupling and metabolic pathways, accompanied by activation of inflammatory and fibrotic signaling. Notably, partial loss of Erk1 further exacerbated mortality and cardiac dysfunction in SM22α-E2KO mice, indicating a compensatory role of ERK1 in the setting of ERK2 deficiency. Collectively, these findings identify ERK2 signaling in VSMCs as a critical determinant of vascular tone and cardiac systolic function and demonstrate that combined vascular and myocardial ERK2 deficiency promotes heart failure through Rho-kinase-dependent vascular dysfunction.