Mechano‐sensing and transduction by endothelial surface glycocalyx: composition, structure, and function

The endothelial cells (ECs) lining every blood vessel wall are constantly exposed to the mechanical forces generated by blood flow. The EC responses to these hemodynamic forces play a critical role in the homeostasis of the circulatory system. To ensure proper EC mechano‐sensing and transduction, there are a variety of mechano‐sensors and transducers that have been identified on the EC surface, intra‐ and trans‐EC membrane and within the EC cytoskeleton. Among them, the most recent candidate is the endothelial surface glycocalyx (ESG), which is a matrix‐like thin layer covering the luminal surface of the EC. It consists of various proteoglycans, glycosaminoglycans, and plasma proteins, and is close to other prominent EC mechano‐sensors and transducers. The ESG thickness was found to be in the order of 0.1–1 µm by different visualization techniques and in different types of vessels. Detailed analysis on the electron microscopy (EM) images of the microvascular ESG revealed a quasi‐periodic substructure with the ESG fiber diameter of 10–12 and 20 nm spacing between adjacent fibers. Atomic force microscopy and optical tweezers were applied to investigate the mechanical properties of the ESG on the cultured EC monolayers and in solutions. Enzymatic degradation of specific ESG glycosaminoglycan components was used to directly elucidate the role of the ESG in EC mechano‐sensing and transduction by measuring the shear‐induced productions of nitric oxide and prostacyclin, two characteristic responses of the ECs to the flow. The unique location, composition, and structure of the ESG determine its role in EC mechano‐sensing and transduction. WIREs Syst Biol Med 2013, 5:381–390. doi: 10.1002/wsbm.1211

[1]  A. Pries,et al.  Effect of the endothelial surface layer on transmission of fluid shear stress to endothelial cells. , 2001, Biorheology.

[2]  A. Barakat,et al.  Flow-activated Chloride Channels in Vascular Endothelium , 2006, Journal of Biological Chemistry.

[3]  Sheldon Weinbaum,et al.  The role of the glycocalyx in reorganization of the actin cytoskeleton under fluid shear stress: a "bumper-car" model. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[4]  V. Hlady,et al.  Stiffness and heterogeneity of the pulmonary endothelial glycocalyx measured by atomic force microscopy. , 2011, American journal of physiology. Lung cellular and molecular physiology.

[5]  B. Fu,et al.  Adhesion of malignant mammary tumor cells MDA-MB-231 to microvessel wall increases microvascular permeability via degradation of endothelial surface glycocalyx. , 2012, Journal of applied physiology.

[6]  Jeffry A Florian,et al.  Heparan Sulfate Proteoglycan Is a Mechanosensor on Endothelial Cells , 2003, Circulation research.

[7]  R. Busse,et al.  Vasoconstriction and increased flow: two principal mechanisms of shear stress-dependent endothelial autacoid release. , 1993, The American journal of physiology.

[8]  J. Squire,et al.  Similar endothelial glycocalyx structures in microvessels from a range of mammalian tissues: evidence for a common filtering mechanism? , 2011, Biophysical journal.

[9]  A. Pries,et al.  Corrections and Retraction , 2004 .

[10]  L. Bourguignon,et al.  CD44 interaction with ankyrin and IP3 receptor in lipid rafts promotes hyaluronan-mediated Ca2+ signaling leading to nitric oxide production and endothelial cell adhesion and proliferation. , 2004, Experimental cell research.

[11]  B. Duling,et al.  Identification of distinct luminal domains for macromolecules, erythrocytes, and leukocytes within mammalian capillaries. , 1996, Circulation research.

[12]  C. P. Winlove,et al.  Effects of perfusate composition on binding of ruthenium red and gold colloid to glycocalyx of rabbit aortic endothelium. , 1984, The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society.

[13]  L V McIntire,et al.  Flow effects on prostacyclin production by cultured human endothelial cells. , 1985, Science.

[14]  Bin Cai,et al.  Quantification of the endothelial surface glycocalyx on rat and mouse blood vessels. , 2012, Microvascular research.

[15]  M. Gimbrone,et al.  Influence of hemodynamic forces on vascular endothelial function. In vitro studies of shear stress and pinocytosis in bovine aortic cells. , 1984, The Journal of clinical investigation.

[16]  Sheldon Weinbaum,et al.  The structure and function of the endothelial glycocalyx layer. , 2007, Annual review of biomedical engineering.

[17]  D. Mizuno,et al.  Viscoelastic response of a model endothelial glycocalyx , 2009, Physical biology.

[18]  Stephen C. Cowin,et al.  Mechanotransduction and flow across the endothelial glycocalyx , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[19]  J. Esko,et al.  Heparan sulfate proteoglycans. , 2011, Cold Spring Harbor perspectives in biology.

[20]  Hans Vink,et al.  The Endothelial Glycocalyx Protects Against Myocardial Edema , 2003, Circulation research.

[21]  H. H. Lipowsky,et al.  Composition of the endothelial glycocalyx and its relation to its thickness and diffusion of small solutes. , 2010, Microvascular research.

[22]  D. Sims,et al.  Non-aqueous fixative preserves macromolecules on the endothelial cell surface: an in situ study. , 1993, European Journal of Morphology.

[23]  B. Haraldsson,et al.  A quantitative analysis of the glomerular charge barrier in the rat. , 2001, American journal of physiology. Renal physiology.

[24]  Jason R. Kosky,et al.  The role of endothelial glycocalyx components in mechanotransduction of fluid shear stress. , 2007, Biochemical and biophysical research communications.

[25]  D. Slaaf,et al.  Endothelial Glycocalyx Structure in the Intact Carotid Artery: A Two-Photon Laser Scanning Microscopy Study , 2011, Journal of Vascular Research.

[26]  S. Weinbaum,et al.  Large-deformation analysis of the elastic recoil of fibre layers in a Brinkman medium with application to the endothelial glycocalyx , 2006, Journal of Fluid Mechanics.

[27]  Donald E. Ingber,et al.  Mechanosensitive mechanisms in transcriptional regulation , 2012, Journal of Cell Science.

[28]  B. Haraldsson,et al.  A gel-membrane model of glomerular charge and size selectivity in series. , 2001, American journal of physiology. Renal physiology.

[29]  Douglas W DeSimone,et al.  Cell adhesion receptors in mechanotransduction. , 2008, Current opinion in cell biology.

[30]  A. Barakat,et al.  Vascular endothelial wound closure under shear stress: role of membrane fluidity and flow-sensitive ion channels. , 2005, Journal of applied physiology.

[31]  B. Hierck,et al.  Primary cilia as biomechanical sensors in regulating endothelial function. , 2012, Differentiation; research in biological diversity.

[32]  J. Squire,et al.  Quasi-periodic substructure in the microvessel endothelial glycocalyx: a possible explanation for molecular filtering? , 2001, Journal of structural biology.

[33]  D. Slaaf,et al.  Two-Photon Microscopy of Vital Murine Elastic and Muscular Arteries , 2006, Journal of Vascular Research.

[34]  P. Butler,et al.  Endothelial Cell Membrane Sensitivity to Shear Stress is Lipid Domain Dependent , 2011, Cellular and molecular bioengineering.

[35]  F. Kajiya,et al.  Role of hyaluronic acid glycosaminoglycans in shear-induced endothelium-derived nitric oxide release. , 2003, American journal of physiology. Heart and circulatory physiology.

[36]  Donald E Ingber,et al.  Mechanobiology and diseases of mechanotransduction , 2003, Annals of medicine.

[37]  David C Spray,et al.  Imaging the Endothelial Glycocalyx In Vitro by Rapid Freezing/Freeze Substitution Transmission Electron Microscopy , 2011, Arteriosclerosis, thrombosis, and vascular biology.

[38]  R. Adamson,et al.  Plasma proteins modify the endothelial cell glycocalyx of frog mesenteric microvessels. , 1992, The Journal of physiology.

[39]  Joshua T. Morgan,et al.  Nesprin-3 regulates endothelial cell morphology, perinuclear cytoskeletal architecture, and flow-induced polarization , 2011, Molecular biology of the cell.

[40]  S. Chien.  Mechanotransduction and endothelial cell homeostasis: the wisdom of the cell. , 2007, American journal of physiology. Heart and circulatory physiology.

[41]  J. Tarbell,et al.  Mechanotransduction and the glycocalyx , 2006, Journal of internal medicine.

[42]  E. Tkachenko,et al.  Syndecans: new kids on the signaling block. , 2005, Circulation research.

[43]  Wen Wang,et al.  Spatio-temporal development of the endothelial glycocalyx layer and its mechanical property in vitro , 2012, Journal of The Royal Society Interface.

[44]  M. Kanzaki,et al.  Non-muscle myosin II induces disassembly of actin stress fibres independently of myosin light chain dephosphorylation , 2011, Interface Focus.

[45]  W. Yang,et al.  From hemorheology to vascular mechanobiology: An overview. , 2004, Clinical hemorheology and microcirculation.

[46]  C Forbes Dewey,et al.  Glycocalyx modulates the motility and proliferative response of vascular endothelium to fluid shear stress. , 2007, American journal of physiology. Heart and circulatory physiology.

[47]  C. Michel,et al.  Inflammatory changes in permeability and ultrastructure of single vessels in the frog mesenteric microcirculation. , 1988, The Journal of physiology.

[48]  J. Squire,et al.  3D Reconstruction of the Glycocalyx Structure in Mammalian Capillaries using Electron Tomography , 2012, Microcirculation.

[49]  K. Ley,et al.  Near-wall micro-PIV reveals a hydrodynamically relevant endothelial surface layer in venules in vivo. , 2003, Biophysical journal.

[50]  J. Tarbell,et al.  The Endothelial Glycocalyx: A Mechano-Sensor and -Transducer , 2008, Science Signaling.

[51]  David S. Long,et al.  Near-Wall μ-PIV Reveals a Hydrodynamically Relevant Endothelial Surface Layer in Venules In Vivo , 2003 .

[52]  J. J. Schwartz,et al.  Heparan sulfate proteoglycans of the cardiovascular system. Specific structures emerge but how is synthesis regulated? , 1997, The Journal of clinical investigation.

[53]  K. Qvortrup,et al.  Electron microscopic demonstrations of filamentous molecular sieve plugs in capillary fenestrae. , 1997, Microvascular research.

[54]  D. Ingber,et al.  Mechanotransduction at a distance: mechanically coupling the extracellular matrix with the nucleus , 2009, Nature Reviews Molecular Cell Biology.

[55]  B. Döme,et al.  Expression of CD44v3 protein in human endothelial cells in vitro and in tumoral microvessels in vivo. , 2004, Microvascular research.

[56]  PECAM-1 is a critical mediator of atherosclerosis , 2008, Disease Models & Mechanisms.

[57]  J. Ando,et al.  New molecular mechanisms for cardiovascular disease:blood flow sensing mechanism in vascular endothelial cells. , 2011, Journal of pharmacological sciences.

[58]  J. Spaan,et al.  Impaired glycocalyx barrier properties contribute to enhanced intimal low-density lipoprotein accumulation at the carotid artery bifurcation in mice , 2009, Pflügers Archiv - European Journal of Physiology.

[59]  J. Tarbell,et al.  The Structural Stability of the Endothelial Glycocalyx after Enzymatic Removal of Glycosaminoglycans , 2012, PloS one.

[60]  T. W. Secomb,et al.  The endothelial surface layer , 2000, Pflügers Archiv.

[61]  E. Bassenge,et al.  EDRF-mediated shear-induced dilation opposes myogenic vasoconstriction in small rabbit arteries. , 1991, The American journal of physiology.

[62]  B. Haraldsson,et al.  The glomerular endothelial cell coat is essential for glomerular filtration. , 2011, Kidney international.

[63]  P. Davies,et al.  Flow-mediated endothelial mechanotransduction. , 1995, Physiological reviews.