Patient vascular model reveals anti-inflammatory effects of SGLT2 inhibitor by modulating endothelial-T cell crosstalk

Abstract Metabolic syndrome (MetS) is a cluster of conditions including obesity, insulin resistance, hypertension and dyslipidemia, that significantly increase cardiovascular disease (CVD) risk. Diabetes and metabolic dysfunction-associated steatotic liver disease (MASLD) are highly prevalent in MetS, with growing evidence highlighting their role in amplifying atherosclerosis and cardiovascular events. MetS-driven systemic inflammation exacerbates endothelial dysfunction, a key factor contributing to vascular complications. Among available therapies, sodium-glucose cotransporter 2 inhibitors (SGLT2i) have demonstrated cardiometabolic benefits beyond glucose control in MetS patients, yet its effects on endothelial function and endothelial-immune interaction that is critical in inflammation remain understudied. Using dapagliflozin as a reference drug, our study investigates SGLT2i’s effects on endothelial dysfunction. We hypothesize that the drug’s cardiometabolic benefits are, in part, mediated by its anti-inflammatory effects on the endothelium, modulating endothelial-immune crosstalk to resolve vascular inflammation. In a clinical trial involving drug-naïve MetS patients, 3-month dapagliflozin treatment not only improved HbA1c, lipid profile and body mass index but also reduced circulating endothelial cells, a biomarker of endothelial dysfunction, indicating potential vascular repair beyond metabolic benefits. In vitro, we generated blood outgrowth endothelial cells (BOEC) from MetS patients and tested dapagliflozin’s anti-inflammatory effects. Treatment of BOEC with dapagliflozin-exposed plasma showed drug-associated modulation of endothelial chemokine, signifying indirect drug actions through improved peripheral indicators. To examine direct drug actions, we first confirmed SGLT2 receptor expression on BOEC using immunofluorescence. Thereafter, direct drug treatment on BOEC monolayer revealed alterations to endothelial chemokine expression, which, in a dynamic flow culture system, was found to implicate endothelial-T interactions and improved endothelial permeability, thereby demonstrating a functional benefit independent of direct immunomodulation. Given the heterogenous clinical presentation of MetS, we focused on MASLD, its hepatic manifestation. Leveraging on a 3D microfluidic chip, we cocultured BOEC with T and human hepatocytes to interrogate dapagliflozin’s effect on endothelial-immune interactions in a liver-relevant microenvironment. In summary, findings from MetS BOEC offer critical insights into dapagliflozin’s effects on endothelial dysfunction and immune crosstalk in resolving vascular inflammation while underscoring the potential for personalized drug interventions. Notably, our integration of microfluidics paves way for advanced biological discoveries and preclinical vascular disease modelling to facilitate the development of therapies for MetS-associated vascular dysfunctions.