Endothelial S1PR3 downregulation exacerbates pressure overload-induced cardiac remodeling by promoting fibrosis and inflammation.

Endothelial dysfunction and inflammation are pivotal contributors to pathological cardiac remodeling and its progression toward heart failure (HF). Sphingosine-1-phosphate receptor 3 (S1PR3), a G protein-coupled receptor enriched in endothelial cells (ECs), is an important regulator of endothelial function, but its role in pressure overload-induced cardiac remodeling remains unclear. In this study, we observed a substantial reduction in S1PR3 levels in cardiac ECs following transverse aortic constriction (TAC). Endothelial-targeted S1PR3 knockdown aggravated TAC-induced cardiac remodeling, as evidenced by aggravated myocardial fibrosis, cardiac hypertrophy, microvascular rarefaction, and inflammatory cell infiltration. Mechanistically, both in vitro and in vivo analyses showed that S1PR3 deficiency promoted endothelial inflammatory activation and NF-κB-associated signaling, and altered endothelial paracrine communication with cardiac fibroblasts and cardiomyocytes, thereby contributing to fibroblast activation and cardiomyocyte hypertrophy under pathological stress. Conversely, endothelial S1PR3 overexpression alleviated TAC-induced cardiac remodeling. Importantly, pharmacological activation of S1PR3 with CYM-5541 also attenuated functional impairment, reduced fibrosis and hypertrophy, preserved myocardial microvascular density, and suppressed inflammatory responses after TAC. Collectively, our findings identify endothelial S1PR3 as a protective regulator in pressure overload-induced cardiac remodeling and support S1PR3 as a potential therapeutic target for limiting maladaptive cardiac remodeling.