| Autor: |
Nakayama KH; 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., Surya VN; Stanford Cardiovascular Institute , Stanford, California 94305, United States.; Department of Chemical Engineering, Stanford University School of Engineering , Stanford, California 94305, United States., Gole M; Veterans Affairs Palo Alto Health Care System , Palo Alto, California 94304, United States., Walker TW; Department of Chemical Engineering, Oregon State University , Corvallis, Oregon 97331, United States., Yang W; Department of Pediatrics, Stanford School of Medicine , Stanford, California 94305, United States., Lai ES; Department of Chemical Engineering, Stanford University School of Engineering , Stanford, California 94305, United States., Ostrowski MA; Department of Chemical Engineering, Stanford University School of Engineering , Stanford, California 94305, United States., Fuller GG; Department of Chemical Engineering, Stanford University School of Engineering , Stanford, California 94305, United States., Dunn AR; Stanford Cardiovascular Institute , Stanford, California 94305, United States.; Department of Chemical Engineering, Stanford University School of Engineering , Stanford, California 94305, United States., Huang NF; 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. |
| Abstrakt: |
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. |
