Recapitulating physiological and pathological shear stress and oxygen to model vasculature in health and disease.
Recapitulating physiological and pathological shear stress and oxygen to model vasculature in health and disease.
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DOI：
10.1038/srep04951
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发表时间：
2014-05-13
影响因子：
4.6
通讯作者：
Gerecht S
中科院分区：
文献类型：
--
作者：
Abaci HE;Shen YI;Tan S;Gerecht S
在传统细胞培养和动物模型中研究人类血管疾病并不能有效地模拟复杂的血管微环境，也可能无法准确预测人类的血管反应。我们利用微流控装置来重现健康和疾病中的剪切应力和O2水平，建立微流控血管模型（μVM）。维持人内皮细胞（EC）在健康的模仿条件下，导致转换为生理表型，即细胞伸长，增殖减少，降低血管生成基因的表达和形成肌动蛋白皮质边缘和连续的屏障。接下来，我们检查了健康μVM对血管毒性癌症药物5-氟尿嘧啶（5-FU）的反应，并与体内小鼠模型进行比较。我们发现，5-FU并不诱导细胞凋亡，而血管通透性增高，这可以减轻白藜芦醇治疗。体内研究结果证实了这种作用，通过5-FU与白藜芦醇的辅助治疗确定了血管保护策略。缺血性疾病的μVM表明EC从静止状态转变为活化状态，具有更高的增殖率、血管生成基因的上调和屏障完整性受损。μVM提供了在健康、病理和药物治疗环境中研究和预测具有生理相关表型的人类EC的机会。
Studying human vascular disease in conventional cell cultures and in animal models does not effectively mimic the complex vascular microenvironment and may not accurately predict vascular responses in humans. We utilized a microfluidic device to recapitulate both shear stress and O2 levels in health and disease, establishing a microfluidic vascular model (μVM). Maintaining human endothelial cells (ECs) in healthy-mimicking conditions resulted in conversion to a physiological phenotype namely cell elongation, reduced proliferation, lowered angiogenic gene expression and formation of actin cortical rim and continuous barrier. We next examined the responses of the healthy μVM to a vasotoxic cancer drug, 5-Fluorouracil (5-FU), in comparison with an in vivo mouse model. We found that 5-FU does not induce apoptosis rather vascular hyperpermeability, which can be alleviated by Resveratrol treatment. This effect was confirmed by in vivo findings identifying a vasoprotecting strategy by the adjunct therapy of 5-FU with Resveratrol. The μVM of ischemic disease demonstrated the transition of ECs from a quiescent to an activated state, with higher proliferation rate, upregulation of angiogenic genes, and impaired barrier integrity. The μVM offers opportunities to study and predict human ECs with physiologically relevant phenotypes in healthy, pathological and drug-treated environments.
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影响因子：
12.3
作者：
Carpenter AE;Jones TR;Lamprecht MR;Clarke C;Kang IH;Friman O;Guertin DA;Chang JH;Lindquist RA;Moffat J;Golland P;Sabatini DM
通讯作者：
Sabatini DM
DOI：
10.1161/atvbaha.112.252080
发表时间：
2012-08-01
影响因子：
8.7
作者：
Fernandez-Martin, Laura;Marcos-Ramiro, Beatriz;Millan, Jaime
通讯作者：
Millan, Jaime
影响因子：
4
作者：
dela Paz, Nathaniel G.;Walshe, Tony E.;D'Amore, Patricia A.
通讯作者：
D'Amore, Patricia A.
影响因子：
20.3
作者：
Dekker, RJ;van Soest, S;Horrevoets, AJG
通讯作者：
Horrevoets, AJG
DOI：
10.1073/pnas.041359198
发表时间：
2001-02-27
影响因子：
11.1
作者：
Fukumura, D;Gohongi, T;Jain, RK
通讯作者：
Jain, RK