由于内膜增生和再狭窄,有创冠状动脉介入治疗可能会失败。内皮细胞(EC)接种到血管腔,加速再内皮化,或局部释放mTOR通路抑制剂有助于减少血管损伤后的内膜增生。虽然动物模型是强大的工具,它们既复杂又昂贵,并不总是反映人体生理。因此,我们开发了一种体外3D血管模型,验证了以前的体内动物模型,并利用离体的人动脉研究了损伤后的血管重构.
我们利用能够控制血管导管中的壁内压力和剪切应力的生物反应器来研究大鼠和人动脉对管腔内损伤的血管反应。
体外培养大鼠主动脉段,我们表明,剧烈去除管腔内皮细胞会导致血管损伤,通过第4天和新内膜形成引起内侧增生,在第7天,在没有血流的情况下,在内膜中观察到SCA1细胞(干细胞抗原-1)。相反,当内皮剥脱的大鼠主动脉和人脐动脉受到动脉剪切应力时,在大鼠和人血管的培养基中,预先接种人脐EC可显着降低平滑肌细胞(SMC)的数量和增殖。
我们的生物反应器系统提供了将离体发现与体内血管结果相关联的新平台。目前的体外人动脉损伤模型有助于研究EC-SMC相互作用和血管重构,通过允许机械的分离,细胞,和可溶性因素。
Invasive coronary interventions can fail due to intimal hyperplasia and restenosis. Endothelial cell (EC) seeding to the vessel lumen, accelerating re-endothelialization, or local release of mTOR pathway inhibitors have helped reduce intimal hyperplasia after vessel injury. While animal models are powerful tools, they are complex and expensive, and not always reflective of human physiology. Therefore, we developed an in vitro 3D vascular model validating previous in vivo animal models and utilizing isolated human arteries to study vascular remodeling after injury.
We utilized a bioreactor that enables the control of intramural pressure and shear stress in vessel conduits to investigate the vascular response in both rat and human arteries to intraluminal injury.
Culturing rat aorta segments in vitro, we show that vigorous removal of luminal ECs results in vessel injury, causing medial proliferation by Day-4 and neointima formation, with the observation of SCA1+ cells (stem cell antigen-1) in the intima by Day-7, in the absence of flow. Conversely, when endothelial-denuded rat aortae and human umbilical arteries were subjected to arterial shear stress, pre-seeding with human umbilical ECs decreased the number and proliferation of smooth muscle cell (SMC) significantly in the media of both rat and human vessels.
Our bioreactor system provides a novel platform for correlating ex vivo findings with vascular outcomes in vivo. The present in vitro human arterial injury model can be helpful in the study of EC-SMC interactions and vascular remodeling, by allowing for the separation of mechanical, cellular, and soluble factors.