Modeling smooth muscle cell-endothelial cell crosstalk in abdominal aortic aneurysms using 3D microvessels on-chip.

Abdominal aortic aneurysms (AAAs) are pathological dilations of the abdominal aorta. To date, surgical intervention has been the only option for managing large AAAs, with no pharmacological therapies to prevent growth of small aneurysms. A current limitation in investigating further pharmacological avenues is the translatability of results from either animal models or patient trials that are limited by co-morbidities and disease severity. To bridge this knowledge gap, we created a novel patient-specific vessel-on-chip (VoC) model of the microcirculation in AAA (AAA-VoC), to specifically address VSMC-EC crosstalk. We found that co-culture of both C (control)-VSMCs and AAA-patient-derived VSMCs with healthy, hiPSC-derived ECs generate lumenized and perfusable microvascular networks. We show that AAA-VoCs are characterized by an enlarged average vascular diameter. We furthermore found that AAA-VSMCs show phenotypical deviations from C-VSMCs after 7 days in co-culture such as increased number and surface area, indicative of a preserved pathological phenotype in our in vitro model. Finally, we demonstrate that AAA-VoCs show an elevated level of pro-inflammatory cytokine expression and an impaired endothelial barrier function, resulting in vascular leakage. With this study, we show that AAA-VSMCs affect microvascular networks formed by healthy hiPSC-ECs and that a AAA-VSMC phenotype is preserved in 3D co-culture, making this model valuable for future studies investigating treatments for AAA.