Endothelial LRRC8A mitigates pressure overload-induced cardiac hypertrophy by promoting coronary angiogenesis.

OBJECTIVE

Clinical evidence has indicated that pressure overload-induced cardiac hypertrophy is closely linked with adverse cardiac outcomes. Endothelial dysfunction is a key contributor to the progression of cardiac hypertrophy and heart failure (HF). Although leucine-rich repeat-containing 8A (LRRC8A) serves as a critical regulator of vascular endothelial homeostasis, its functional role in pressure overload-induced pathological hypertrophy and dysfunction remains unclear. In this study, we aimed to investigate the role and mechanism of endothelial LRRC8A in pressure overload-induced pathological hypertrophy.

METHODS AND

RESULTS

Here, we found that LRRC8A expression was markedly downregulated in hypertrophic hearts and cardiac endothelial cells (CECs) from both patients and mice. Endothelial LRRC8A knockout mice exhibited exacerbated pathological hypertrophy and dysfunction following transverse aortic constriction (TAC) surgery. Moreover, single-cell RNA sequencing (scRNA-seq) analysis revealed that LRRC8A-deficient CECs displayed downregulation of gene programs related to angiogenesis, migration, and proliferation. Consistently, endothelial LRRC8A deficiency reduced capillary density in TAC hearts in vivo and inhibited endothelial cell (EC) tube formation, migration, and proliferation in vitro. Mechanistically, LRRC8A positively regulated the VEGF-VEGFR2 axis, interacted with VEGFR2, and promoted VEGFR2 endocytosis. Therapeutically, AAV9-ICAM2-LRRC8A gene therapy restored coronary angiogenesis and ameliorated TAC-induced hypertrophy and dysfunction.

CONCLUSION

Our findings identify endothelial LRRC8A as a critical regulator of coronary angiogenesis in pressure overload-induced hypertrophic hearts and indicate that it could serve as a therapeutic target for cardiac hypertrophy and HF.