Platelet mechanosensing and activation
The platelet glycoprotein (GP) Ib-IX complex is the primary platelet mechanosensor. It senses blood flow through its engagement with the VWF A1 domain and transmits a signal into the platelet. Collaborating with Dr. Renhao Li at Emory, I recently identified a quasi-stable mechanosensitive domain (MSD) of approximately 60 residues between the macroglycopeptide region and the transmembrane helix of the GPIba subunit. The MSD unfolds at 5–20 pN when subjected to mechanical stretch by the engaged A1. Unfolding the MSD triggers receptor signaling and stimulates platelets. This new mechanosensing mechanism may have important implications for the platelet clearance mechanism and the pathogenesis of a number of bleeding disorders such as immune thrombocytopenia.
Endothelial mechanosensing and mechanotransduction
The second project on this theme is to elucidate the molecular mechanisms of endothelial surface glycocalyx (ESG)-mediated mechanotransduction. ESG is a carbohydrate-rich layer found on the vascular endothelium that provides a multifunctional protective coating of the vasculature’s inner lumen. Composed of membrane glycoproteins, glycosaminoglycans (GAGs), such as hyaluronan and heparan sulfate, and proteoglycans, the ESG forms a bulky, gel-like layer, serving critical functions in blood flow mechanotransduction, endothelial permeability maintenance, and leukocyte adhesion and inflammation control (Fig. A). Although it has been known for decades that ESG senses blood flow and transduces the mechanical signal into nitric oxide production—an essential signaling molecule to regulate vascular tone—the molecular pathways of ESG-mediated mechanotransduction have not yet been discovered.
Our research group can precisely control force onto a single live endothelial cell using our home-built mechanotransduction platform and record calcium entry and nitric oxide production simultaneously (Fig. B-D). Our recent discoveries support the existence of a functional mechanotransduction unit on the endothelial surface. This mechanotransduction unit consists of ESG and one or more of its core proteins (e.g., CD44, glypicans, or syndecans), mechanosensitive channels (e.g., transient receptor potential channels), and endothelial nitric oxide synthase, with all these components co-localizing within the caveolae (Fig. A). This hypothesis is being actively tested.
We are also working on repairing damaged ESG to prevent or treat various cardiovascular diseases using ESG-mimicking soft materials. The majority of cardiovascular diseases (CVDs) are initiated through injury or inflammation in the vascular endothelium, suggesting that efforts to repair damage to the endothelium may prevent and treat CVDs. ESG disruption has been linked to the onset and progression of several CVDs, including sepsis, atherosclerosis, diabetes, and hypertension. Thus, strategies to rebuild the ESG are highly popular. We plan to design, synthesize, and characterize injectable GAG-based molecules that self-assemble into stable, ESG-mimicking hydrogels. We hypothesize that GAGs functionalized with endothelial cell-binding and self-assembling peptides can form hydrogels in situ to reconstruct a disrupted ESG and restore endothelial cell function.
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- Zhang, X.F.* and Cheng, X. (2019): Platelet mechanosensing axis. Nature Materials, 18:661–662.
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- Dong, C., Choi, Y.K., Lee, J., Zhang, X.F., Honerkamp-Smith, A., Göran, W., Lowe-Krentz, L.J. and Im, W. (2020): Structure, Dynamics, and Interactions of GPI-Anchored Human Glypican-1 with Heparan Sulfates in a Membrane. Glycobiology, in press.
- Zheng, Y., Zhang, X.F., Fu, B., and Tarbell, J.M.: (2018): The role of endothelial glycocalyx in mechanosensing and transduction. Advances in Experimental Medicine and Biology, 1097:1-27.
- Zhang, X.F., Sun, D., Song, J.W., Lipphardt, M., Goligorsky, M.S. (2018): Endothelial cell dysfunction and glycocalyx – the vicious circle. Matrix Biology, 71-72:421-431.
- Song, J.W., Zullo, J.A., Lipphardt, M., Dragovich, M., Zhang X.F., Fu, B. and Goligorsky, M. (2018): Endothelial Glycocalyx – the battleground for complications of sepsis and kidney injury. Nephrology Dialysis Transplantation, 33 (2):203–211.
- Song, J.W., Zullo, J.A., Liveris, D., Dragovich, M., Zhang X.F., and Goligorsky, M.S. (2017): Therapeutic Restoration of Endothelial Glycocalyx in Sepsis. The Journal of pharmacology and experimental therapeutics, 361(1):115-121.
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- Dragovich, M.A., Chester, D., Fu, B., Goligorsky, M.S., and X.F.* (2016): Mechanotransduction of endothelial glycocalyx mediates nitric oxide production by activation of TRP channels. AJP – Cell Physiology, 311(6):C846-853.