Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2007 May 8;104(19):7899-903.
doi: 10.1073/pnas.0608422104. Epub 2007 Apr 30.

Shear-induced unfolding triggers adhesion of von Willebrand factor fibers

S W Schneider  1 , S Nuschele, A Wixforth, C Gorzelanny, A Alexander-Katz, R R Netz, M F Schneider
Affiliations

Shear-induced unfolding triggers adhesion of von Willebrand factor fibers

S W Schneider et al. Proc Natl Acad Sci U S A. .

Abstract

von Willebrand factor (VWF), a protein present in our circulatory system, is necessary to stop bleeding under high shear-stress conditions as found in small blood vessels. The results presented here help unravel how an increase in hydrodynamic shear stress activates VWF's adhesion potential, leading to the counterintuitive phenomena of enhanced adsorption rate under strong shear conditions. Using a microfluidic device, we were able to mimic a wide range of bloodflow conditions and directly visualize the conformational dynamics of this protein under shear flow. In particular, we find that VWF displays a reversible globule-stretch transition at a critical shear rate gamma(crit) in the absence of any adsorbing surface. Computer simulations reproduce this sharp transition and identify the large size of VWF's repeating units as one of the keys for this unique hydrodynamic activation. In the presence of an adsorbing collagen substrate, we find a large increase in the protein adsorption at the same critical shear rate, suggesting that the globule unfolding in bulk triggers the surface adsorption in the case of a collagen substrate, which provides a sufficient density of binding sites. Monitoring the adsorption process of multiple VWF fibers, we were able to follow the formation of an immobilized network that constitutes a "sticky" grid necessary for blood platelet adhesion under high shear flow. Because areas of high shear stress coincide with a higher chance for vessel wall damage by mechanical forces, we identified the shear-induced increase in the binding probability of VWF as an effective self-regulating repair mechanism of our microvascular system.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.
Fig. 1.
The planar microfluidic device. The blood vessel is modeled by a planar hydrophilic track on an otherwise hydrophobic piezoelectric substrate. A surface acoustic wave, excited electrically, eventually interacts with the confined liquid at the solid–liquid interface and drives the liquid to flow (acoustic streaming). The surface wave basically acts as a localized pump, because its mechanical energy is absorbed by the liquid over only a few micrometers. Due to the small scales of this microfluidic system, it creates a homogenous laminar flow (low Reynold's number) along the channel, mimicking the blood flow in arteries or capillaries.
Fig. 2.
Fig. 2.
Dynamic conformational change of VWF under shear. (a) Cartoon (Upper) and selected fluorescence (Lower) images of a video sequence (SI Movie 1, acquired at 25 frames per second) of VWF below and above the critical shear rate of a few thousand s−1. Above γ̇crit, the protein is in an elongated conformation. The little yellow spots on the protein are meant to represent a variety of known binding sites. To assure that only unbound VWF was detected, the focus of the microscope was set ≈10 μm above the surface of the chip in the middle of the channel. (b) Relaxation of VWF. Selected fluorescence images of a video sequence (SI Movie 1, acquired at 25 frames per second). Once the hydrodynamic shear force is reduced below γ̇crit at 0 ms, the protein immediately relaxes back to its compact state. The unfolding process is reversible and presumably does not include protein denaturation.
Fig. 3.
Fig. 3.
Typical polymer configurations, coiled (a), collapsed (b), and stretched (c), observed at different solvent conditions and different values of the shear rate [images were selected from our computer simulation (SI Movie 2)]. (d) The experimentally determined average extension (open squares) and the normalized rate of adhesion (filled diamonds) of VWF multimers as a function of the shear rate (SI Movie 3). The vertical dashed line is located at the critical shear rate, and the letters denote the type of prevalent polymer conformation as illustrated in the sketches. (Inset) Simulation results for the normalized extension (equal to the average extension divided by the contour length) of a 50-mer as a function of the dimensionless shear rate γ̇τ (lower scale) and the physical shear rate γ̇ using a monomer size a = 80 nm and a viscosity η = 1 cP (upper scale). The coiled (open circles) and the collapsed (open squares) polymers have an attractive contact potential depth of ΔU = 0.416 and ΔU = 2.08 (in units of kBT), respectively. The vertical dotted and dashed lines correspond to the shear rates at which the coiled and collapsed polymers start exhibiting strong elongations, respectively, as determined by a maximum in the higher-order cumulants. The lines joining the data points are just to guide the eye.
Fig. 4.
Fig. 4.
Adhesion of VWF. (a) Below the critical shear rate γ̇crit, only few VWF coils adhere to the collagen coated surface. (b) VWF adhered at high shear rates forms a spider web like network, which represents a very adhesive substrate for blood platelets.
Fig. 5.
Fig. 5.
Blood platelet –VWF aggregation under high shear flow (γ̇ ≈ 4,000 s−1). Blood platelets (≈1 μm) are immobilized on the free end of a VWF fiber only when γ̇ ≈ 3,500 s−1. The white line indicates the underlying VWF and is given as a guide to the eye (see also SI Fig. 7). (Scale bar, 10 μm.)
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Trusky GA, Yuan F, Katz DF. Transport Phemomena in Biological Systems. Upper Saddle River, New Jersey: Pearson Education; 2004.
    1. Lorz B, Simson R, Nardi J, Sackmann E. Europhys Lett. 2000;51:468–474.
    1. Goldmann AJ, Cox RG, Brenner H. Chem Eng Sci. 1967;22:653–660.
    1. Seifert U. Phys Rev Lett. 1999;83:876–879.
    1. Ruggeri ZM. J Clin Invest. 1997;99:559–564. - PMC - PubMed

Publication types

Substances