title: Recapitulating physiological and pathological shear stress and oxygen to model vasculature in health and disease.
abstract: 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.
authors.affiliation: Department of Chemical and Biomolecular Engineering, Johns Hopkins Physical Science Oncology Center and Institute for NanoBioTechnology, The Johns Hopkins University, 3400 N. Charles St., Baltimore, Maryland 21218, USA.
authors.forename: Hasan Erbil
authors.initials: HE
authors.lastname: Abaci
authors.affiliation: Department of Chemical and Biomolecular Engineering, Johns Hopkins Physical Science Oncology Center and Institute for NanoBioTechnology, The Johns Hopkins University, 3400 N. Charles St., Baltimore, Maryland 21218, USA.
authors.forename: Yu-I
authors.initials: YI
authors.lastname: Shen
authors.affiliation: Department of Chemical and Biomolecular Engineering, Johns Hopkins Physical Science Oncology Center and Institute for NanoBioTechnology, The Johns Hopkins University, 3400 N. Charles St., Baltimore, Maryland 21218, USA.
authors.forename: Scott
authors.initials: S
authors.lastname: Tan
authors.affiliation: Department of Chemical and Biomolecular Engineering, Johns Hopkins Physical Science Oncology Center and Institute for NanoBioTechnology, The Johns Hopkins University, 3400 N. Charles St., Baltimore, Maryland 21218, USA.
authors.forename: Sharon
authors.initials: S
authors.lastname: Gerecht
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000150:complications; D002199:Capillary Permeability / Q000187:drug effects; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D005472:Fluorouracil / Q000494:pharmacology; D006801:Humans; D007511:Ischemia / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology; D051379:Mice; D046210:Microfluidic Analytical Techniques; D010101:Oxygen Consumption; D000077185:Resveratrol; D013267:Stilbenes / Q000494:pharmacology; D013314:Stress, Mechanical; D014652:Vascular Diseases / Q000378:metabolism* / Q000503:physiopathology
chemical_list: D013267:Stilbenes; D000077185:Resveratrol; D005472:Fluorouracil