title: Nanoscale Patterning of Extracellular Matrix Alters Endothelial Function under Shear Stress.
abstract: The role of nanotopographical extracellular matrix (ECM) cues in vascular endothelial cell (EC) organization and function is not well-understood, despite the composition of nano- to microscale fibrillar ECMs within blood vessels. Instead, the predominant modulator of EC organization and function is traditionally thought to be hemodynamic shear stress, in which uniform shear stress induces parallel-alignment of ECs with anti-inflammatory function, whereas disturbed flow induces a disorganized configuration with pro-inflammatory function. Since shear stress acts on ECs by applying a mechanical force concomitant with inducing spatial patterning of the cells, we sought to decouple the effects of shear stress using parallel-aligned nanofibrillar collagen films that induce parallel EC alignment prior to stimulation with disturbed flow resulting from spatial wall shear stress gradients. Using real time live-cell imaging, we tracked the alignment, migration trajectories, proliferation, and anti-inflammatory behavior of ECs when they were cultured on parallel-aligned or randomly oriented nanofibrillar films. Intriguingly, ECs cultured on aligned nanofibrillar films remained well-aligned and migrated predominantly along the direction of aligned nanofibrils, despite exposure to shear stress orthogonal to the direction of the aligned nanofibrils. Furthermore, in stark contrast to ECs cultured on randomly oriented films, ECs on aligned nanofibrillar films exposed to disturbed flow had significantly reduced inflammation and proliferation, while maintaining intact intercellular junctions. This work reveals fundamental insights into the importance of nanoscale ECM interactions in the maintenance of endothelial function. Importantly, it provides new insight into how ECs respond to opposing cues derived from nanotopography and mechanical shear force and has strong implications in the design of polymeric conduits and bioengineered tissues.
authors.affiliation: Stanford Cardiovascular Institute , Stanford, California 94305, United States.|Department of Cardiothoracic Surgery, Stanford School of Medicine , Stanford, California 94305, United States.|Veterans Affairs Palo Alto Health Care System , Palo Alto, California 94304, United States.
authors.forename: Karina H
authors.initials: KH
authors.lastname: Nakayama
authors.affiliation: Stanford Cardiovascular Institute , Stanford, California 94305, United States.|Department of Chemical Engineering, Stanford University School of Engineering , Stanford, California 94305, United States.
authors.forename: Vinay N
authors.initials: VN
authors.lastname: Surya
authors.affiliation: Veterans Affairs Palo Alto Health Care System , Palo Alto, California 94304, United States.
authors.forename: Monica
authors.initials: M
authors.lastname: Gole
authors.affiliation: Department of Chemical Engineering, Oregon State University , Corvallis, Oregon 97331, United States.
authors.forename: Travis W
authors.initials: TW
authors.lastname: Walker
authors.affiliation: Department of Pediatrics, Stanford School of Medicine , Stanford, California 94305, United States.
authors.forename: Weiguang
authors.initials: W
authors.lastname: Yang
authors.affiliation: Department of Chemical Engineering, Stanford University School of Engineering , Stanford, California 94305, United States.
authors.forename: Edwina S
authors.initials: ES
authors.lastname: Lai
authors.affiliation: Department of Chemical Engineering, Stanford University School of Engineering , Stanford, California 94305, United States.
authors.forename: Maggie A
authors.initials: MA
authors.lastname: Ostrowski
authors.affiliation: Department of Chemical Engineering, Stanford University School of Engineering , Stanford, California 94305, United States.
authors.forename: Gerald G
authors.initials: GG
authors.lastname: Fuller
authors.affiliation: Stanford Cardiovascular Institute , Stanford, California 94305, United States.|Department of Chemical Engineering, Stanford University School of Engineering , Stanford, California 94305, United States.
authors.forename: Alexander R
authors.initials: AR
authors.lastname: Dunn
authors.affiliation: Stanford Cardiovascular Institute , Stanford, California 94305, United States.|Department of Cardiothoracic Surgery, Stanford School of Medicine , Stanford, California 94305, United States.|Veterans Affairs Palo Alto Health Care System , Palo Alto, California 94304, United States.
authors.forename: Ngan F
authors.initials: NF
authors.lastname: Huang
mesh_terms: D001808:Blood Vessels / Q000737:chemistry; D002465:Cell Movement; D049109:Cell Proliferation; D058948:Cell Tracking; D003094:Collagen / Q000737:chemistry; D042783:Endothelial Cells / Q000737:chemistry* / Q000378:metabolism; D005109:Extracellular Matrix / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D057139:Nanofibers / Q000737:chemistry; D013314:Stress, Mechanical; D023822:Tissue Engineering
chemical_list: D003094:Collagen
keywords: Nanofibrillar scaffold; collagen; endothelial cell; inflammation; patterning