SMOC1 Regulates Endothelial-to-Mesenchymal Transition During Cardiac Repair After Myocardial Infarction

Abstract

Endothelial-to-mesenchymal transition (EndMT) is a crucial, dual-phase process in cardiac repair after myocardial infarction (MI), driving both initial scar stabilization and subsequent pathological fibrosis. Therapeutic targeting requires precise temporal control rather than complete inhibition. This study identifies the matricellular protein SPARC-related modular calcium-binding protein 1 (SMOC1) as a novel regulator of EndMT. Analysis of single-cell RNA sequencing data from post-MI mouse hearts revealed that SMOC1 is highly enriched in a subpopulation of endothelial cells undergoing late EndMT. In vitro, SMOC1 expression was upregulated during cytokine-induced EndMT in human endothelial cells. Its siRNA-mediated knockdown exacerbated the EndMT phenotype, increasing mesenchymal marker expression and cell morphology changes, effects rescued by recombinant SMOC1 (rSMOC1). Mechanistically, SMOC1 deficiency enhanced TGF-{beta}2-induced SMAD2 phosphorylation, while rSMOC1 attenuated this pathway and promoted a shift from the short to the long, signaling-competent isoform of endoglin. In vivo, endothelial-specific SMOC1 deficiency (SMOC1{Delta}EC) in mice promoted age-associated EndMT and profoundly worsened post-MI outcomes. After MI, SMOC1{Delta}EC mice exhibited exacerbated cardiac dysfunction, ventricular dilation, pathological fibrosis, increased inflammatory cell infiltration, reduced survival, and a higher incidence of cardiac rupture compared to controls. Collectively, these findings establish SMOC1 as a critical endogenous modulator of EndMT that restrains its pathological progression. SMOC1 coordinates endothelial cell phenotype, in part by fine-tuning TGF-{beta}/endoglin signaling, and its loss accelerates maladaptive remodeling post-MI. Thus, SMOC1 represents a potential therapeutic target for spatially and temporally controlling EndMT to improve cardiac repair