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The Glycocalyx and Its Role in Vascular Physiology and Vascular Related Diseases

  • John Tarbell
  • Published:
Cardiovascular Engineering and Technology Aims and scope Submit manuscript

Abstract

Purpose

In 2007 the two senior authors wrote a review on the structure and function of the endothelial glycocalyx layer (Weinbaum in Annu Rev Biomed Eng 9:121–167, 2007). Since then there has been an explosion of interest in this hydrated gel-like structure that coats the luminal surface of endothelial cells that line our vasculature due to its important functions in (A) basic vascular physiology and (B) vascular related diseases. This review will highlight the major advances that have occurred since our 2007 paper.

Methods

A literature search mainly focusing on the role of the glycocalyx in the two major areas described above was performed using electronic databases.

Results

In part (A) of this review, the new formulation of the century old Starling principle, now referred to as the Michel–Weinbaum glycoclayx model or revised Starling hypothesis, is described including new subtleties and physiological ramifications. New insights into mechanotransduction and release of nitric oxide due to fluid shear stress sensed by the glycocalyx are elaborated. Major advances in understanding the organization and function of glycocalyx components, and new techniques for measuring both its thickness and spatio-chemical organization based on super resolution, stochastic optical reconstruction microscopy (STORM) are presented. As discussed in part (B) of this review, it is now recognized that artery wall stiffness associated with hypertension and aging induces glycocalyx degradation, endothelial dysfunction and vascular disease. In addition to atherosclerosis and cardiovascular diseases, the glycocalyx plays an important role in lifestyle related diseases (e.g., diabetes) and cancer. Infectious diseases including sepsis, Dengue, Zika and Corona viruses, and malaria also involve the glycocalyx. Because of increasing recognition of the role of the glycocalyx in a wide range of diseases, there has been a vigorous search for methods to protect the glycocalyx from degradation or to enhance its synthesis in disease environments.

Conclusion

As we have seen in this review, many important developments in our basic understanding of GCX structure, function and role in diseases have been described since the 2007 paper. The future is wide open for continued GCX research.

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References

  1. Adamson, R. H., J. F. Lenz, X. Zhang, G. N. Adamson, S. Weinbaum, and F. E. Curry. Oncotic pressures opposing filtration across non-fenestrated rat microvessels. J. Physiol. 557(Pt 3):889–907, 2004.

    Google Scholar 

  2. Adembri, C., E. Sgambati, L. Vitali, V. Selmi, M. Margheri, A. Tani, et al. Sepsis induces albuminuria and alterations in the glomerular filtration barrier: a morphofunctional study in the rat. Crit. Care 15(6):R277, 2011.

    Google Scholar 

  3. Aird, W. C. The role of the endothelium in severe sepsis and multiple organ dysfunction syndrome. Blood 101(10):3765–3777, 2003.

    Google Scholar 

  4. Alves, N. G., A. N. Trujillo, J. W. Breslin, and S. Y. Yuan. Sphingosine-1-phosphate reduces hemorrhagic shock and resuscitation-induced microvascular leakage by protecting endothelial mitochondrial integrity. Shock. 52(4):423–433, 2019.

    Google Scholar 

  5. Annecke, T., D. Chappell, C. Chen, M. Jacob, U. Welsch, C. P. Sommerhoff, et al. Sevoflurane preserves the endothelial glycocalyx against ischaemia-reperfusion injury. Br. J. Anaesth. 104(4):414–421, 2010.

    Google Scholar 

  6. Baburajeev, C. P., C. D. Mohan, S. Rangappa, D. J. Mason, J. E. Fuchs, A. Bender, et al. Identification of novel class of triazolo-thiadiazoles as potent inhibitors of human heparanase and their anticancer activity. BMC Cancer. 17(1):235, 2017.

    Google Scholar 

  7. Baeyens, N., M. J. Mulligan-Kehoe, F. Corti, D. D. Simon, T. D. Ross, J. M. Rhodes, et al. Syndecan 4 is required for endothelial alignment in flow and atheroprotective signaling. Proc. Natl. Acad. Sci. U S A. 111(48):17308–17313, 2014.

    Google Scholar 

  8. Bailey, C. J. Metformin: effects on micro and macrovascular complications in type 2 diabetes. Cardiovasc. Drugs Ther. 22(3):215–224, 2008.

    Google Scholar 

  9. Bar, A., M. Targosz-Korecka, J. Suraj, B. Proniewski, A. Jasztal, B. Marczyk, et al. Degradation of glycocalyx and multiple manifestations of endothelial dysfunction coincide in the early phase of endothelial dysfunction before atherosclerotic plaque development in apolipoprotein E/low-density lipoprotein receptor-deficient mice. J. Am. Heart Assoc. 8(6):e011171, 2019.

    Google Scholar 

  10. Barbareschi, M., P. Maisonneuve, D. Aldovini, M. G. Cangi, L. Pecciarini, F. Angelo Mauri, et al. High syndecan-1 expression in breast carcinoma is related to an aggressive phenotype and to poorer prognosis. Cancer 98(3):474–483, 2003.

    Google Scholar 

  11. Barelli, S., and L. Alberio. The role of plasma transfusion in massive bleeding: protecting the endothelial glycocalyx? Front. Med. (Lausanne). 5:91, 2018.

    Google Scholar 

  12. Bartosch, A. M. W., R. Mathews, and J. M. Tarbell. Endothelial glycocalyx-mediated nitric oxide production in response to selective AFM pulling. Biophys. J. 113(1):101–108, 2017.

    Google Scholar 

  13. Basu, A., M. Du, M. J. Leyva, K. Sanchez, N. M. Betts, M. Wu, et al. Blueberries decrease cardiovascular risk factors in obese men and women with metabolic syndrome. J. Nutr. 140(9):1582–1587, 2010.

    Google Scholar 

  14. Bates, M., B. Huang, G. T. Dempsey, and X. Zhuang. Multicolor super-resolution imaging with photo-switchable fluorescent probes. Science 317(5845):1749–1753, 2007.

    Google Scholar 

  15. Becker, B. F., M. Jacob, S. Leipert, A. H. Salmon, and D. Chappell. Degradation of the endothelial glycocalyx in clinical settings: searching for the sheddases. Br. J. Clin. Pharmacol. 80(3):389–402, 2015.

    Google Scholar 

  16. Bharat, D., R. R. M. Cavalcanti, C. Petersen, N. Begaye, B. R. Cutler, M. M. A. Costa, et al. Blueberry metabolites attenuate lipotoxicity-induced endothelial dysfunction. Mol. Nutr. Food Res. 2018. https://doi.org/10.1002/mnfr.201700601.

    Article  Google Scholar 

  17. Brower, J. B., J. H. Targovnik, M. R. Caplan, and S. P. Massia. High glucose-mediated loss of cell surface heparan sulfate proteoglycan impairs the endothelial shear stress response. Cytoskeleton (Hoboken). 67(3):135–141, 2010.

    Google Scholar 

  18. Buffone, A., and V. M. Weaver. Don’t sugarcoat it: how glycocalyx composition influences cancer progression. J. Cell Biol. 219(1):e201910070, 2020.

    Google Scholar 

  19. Buscail, E., C. Alix-Panabieres, P. Quincy, T. Cauvin, A. Chauvet, O. Degrandi, et al. High clinical value of liquid biopsy to detect circulating tumor cells and tumor exosomes in pancreatic ductal adenocarcinoma patients eligible for up-front surgery. Cancers (Basel). 11(11):1656, 2019.

    Google Scholar 

  20. Butler, M. J., R. Ramnath, H. Kadoya, D. Desposito, A. Riquier-Brison, J. K. Ferguson, et al. Aldosterone induces albuminuria via matrix metalloproteinase-dependent damage of the endothelial glycocalyx. Kidney Int. 95(1):94–107, 2019.

    Google Scholar 

  21. Cai, B., J. Fan, M. Zeng, L. Zhang, and B. M. Fu. Adhesion of malignant mammary tumor cells MDA-MB-231 to microvessel wall increases microvascular permeability via degradation of endothelial surface glycocalyx. J. Appl. Physiol. 113(7):1141–1153, 2012.

    Google Scholar 

  22. Cancel, L. M., E. E. Ebong, S. Mensah, C. Hirschberg, and J. M. Tarbell. Endothelial glycocalyx, apoptosis and inflammation in an atherosclerotic mouse model. Atherosclerosis. 252:136–146, 2016.

    Google Scholar 

  23. Cancel, L. M., and J. M. Tarbell. Rhamnan sulfate enhances the endothelial glycocalyx and decreases the LDL permeability of human coronary artery endothelial cells in vitro. FASEB J. 27:7, 2013. https://doi.org/10.1096/fasebj.27.1_supplement.896.3.

    Article  Google Scholar 

  24. Chappell, D., B. Heindl, M. Jacob, T. Annecke, C. Chen, M. Rehm, et al. Sevoflurane reduces leukocyte and platelet adhesion after ischemia-reperfusion by protecting the endothelial glycocalyx. Anesthesiology 115(3):483–491, 2011.

    Google Scholar 

  25. Chelazzi, C., G. Villa, P. Mancinelli, A. R. De Gaudio, and C. Adembri. Glycocalyx and sepsis-induced alterations in vascular permeability. Crit. Care 19(1):26, 2015.

    Google Scholar 

  26. Chen, Y. T., Z. Chen, and Y. N. Du. Immunohistochemical analysis of RHAMM expression in normal and neoplastic human tissues: a cell cycle protein with distinctive expression in mitotic cells and testicular germ cells. Oncotarget. 9(30):20941–20952, 2018.

    Google Scholar 

  27. Chen, L., X. Li, M. Chen, Y. Feng, and C. Xiong. The ACE2 expression in human heart indicates new potential mechanism of heart injury among patients infected with SARS-CoV-2. Cardiovasc. Res. 116(6):1097–1100, 2020.

    Google Scholar 

  28. Chignalia, A. Z., F. Yetimakman, S. C. Christiaans, S. Unal, B. Bayrakci, B. M. Wagener, et al. The glycocalyx and trauma: a review. Shock. 45(4):338–348, 2016.

    Google Scholar 

  29. Chistiakov, D. A., A. N. Orekhov, and Y. V. Bobryshev. Endothelial PECAM-1 and its function in vascular physiology and atherogenic pathology. Exp. Mol. Pathol. 100(3):409–415, 2016.

    Google Scholar 

  30. Coccheri, S., and F. Mannello. Development and use of sulodexide in vascular diseases: implications for treatment. Drug Des. Devel. Ther. 8:49–65, 2013.

    Google Scholar 

  31. Contreras, H. R., M. Fabre, F. Granes, R. Casaroli-Marano, N. Rocamora, A. G. Herreros, et al. Syndecan-2 expression in colorectal cancer-derived HT-29 M6 epithelial cells induces a migratory phenotype. Biochem. Biophys. Res. Commun. 286(4):742–751, 2001.

    Google Scholar 

  32. Conway, D. E., M. T. Breckenridge, E. Hinde, E. Gratton, C. S. Chen, and M. A. Schwartz. Fluid shear stress on endothelial cells modulates mechanical tension across VE-cadherin and PECAM-1. Curr. Biol. 23(11):1024–1030, 2013.

    Google Scholar 

  33. Coombe, D. R., S. M. Stevenson, B. F. Kinnear, N. S. Gandhi, R. L. Mancera, R. I. Osmond, et al. Platelet endothelial cell adhesion molecule 1 (PECAM-1) and its interactions with glycosaminoglycans: 2. Biochemical analyses. Biochemistry. 47(17):4863–4875, 2008.

    Google Scholar 

  34. Cooper, S., H. Teoh, M. A. Campeau, S. Verma, and R. L. Leask. Empagliflozin restores the integrity of the endothelial glycocalyx in vitro. Mol. Cell. Biochem. 459(1–2):121–130, 2019.

    Google Scholar 

  35. Couchman, J. R., H. Multhaupt, and R. D. Sanderson. Recent insights into cell surface heparan sulphate proteoglycans and cancer. F1000Res. 2016. https://doi.org/10.12688/f1000research.8543.1.

    Article  Google Scholar 

  36. Cui, N., H. Wang, Y. Long, L. Su, and D. Liu. Dexamethasone suppressed LPS-induced matrix metalloproteinase and its effect on endothelial glycocalyx shedding. Mediators Inflamm. 2015:912726, 2015.

    Google Scholar 

  37. Curry, F. E. The molecular structure of the endothelial glycocalyx layer (EGL) and surface layers (ESL) modulation of transvascular exchange. Adv. Exp. Med. Biol. 1097:29–49, 2018.

    Google Scholar 

  38. Cutler, B. R., S. Gholami, J. S. Chua, B. Kuberan, and P. V. Anandh Babu. Blueberry metabolites restore cell surface glycosaminoglycans and attenuate endothelial inflammation in diabetic human aortic endothelial cells. Int. J. Cardiol. 261:155–158, 2018.

    Google Scholar 

  39. Dabagh, M., P. Jalali, P. J. Butler, A. Randles, and J. M. Tarbell. Mechanotransmission in endothelial cells subjected to oscillatory and multi-directional shear flow. J. R. Soc. Interface. 14(130):20170185, 2017.

    Google Scholar 

  40. Danese, C., A. R. Vestri, V. D’Alfonso, G. Deriu, S. Dispensa, R. Baldini, et al. Do hypertension and diabetes mellitus influence the site of atherosclerotic plaques? Clin. Ter. 157(1):9–13, 2006.

    Google Scholar 

  41. Davies, P. F. Hemodynamic shear stress and the endothelium in cardiovascular pathophysiology. Nat. Clin. Pract. Cardiovasc. Med. 6(1):16–26, 2009.

    Google Scholar 

  42. De Rossi, G., A. R. Evans, E. Kay, A. Woodfin, T. R. McKay, S. Nourshargh, et al. Shed syndecan-2 inhibits angiogenesis. J. Cell Sci. 127(Pt 21):4788–4799, 2014.

    Google Scholar 

  43. dela Paz, N. G., B. Melchior, F. Y. Shayo, and J. A. Frangos. Heparan sulfates mediate the interaction between platelet endothelial cell adhesion molecule-1 (PECAM-1) and the Gαq/11 subunits of heterotrimeric G proteins. J. Biol. Chem. 289(11):7413–7424, 2014.

    Google Scholar 

  44. Dogné, S., B. Flamion, and N. Caron. Endothelial glycocalyx as a shield against diabetic vascular complications: involvement of hyaluronan and hyaluronidases. Arterioscler. Thromb. Vasc. Biol. 38(7):1427–1439, 2018.

    Google Scholar 

  45. Dogné, S., G. Rath, F. Jouret, N. Caron, C. Dessy, and B. Flamion. Hyaluronidase 1 deficiency preserves endothelial function and glycocalyx integrity in early streptozotocin-induced diabetes. Diabetes 65(9):2742–2753, 2016.

    Google Scholar 

  46. Duan, L., X. Q. Hu, D. Y. Feng, S. Y. Lei, and G. H. Hu. GPC-1 may serve as a predictor of perineural invasion and a prognosticator of survival in pancreatic cancer. Asian J Surg. 36(1):7–12, 2013.

    Google Scholar 

  47. Dull, R. O., M. Cluff, J. Kingston, D. Hill, H. Chen, S. Hoehne, et al. Lung heparan sulfates modulate K(fc) during increased vascular pressure: evidence for glycocalyx-mediated mechanotransduction. Am. J. Physiol. Lung Cell. Mol. Physiol. 302(9):L816–L828, 2012.

    Google Scholar 

  48. Dull, R. O., I. Mecham, and S. McJames. Heparan sulfates mediate pressure-induced increase in lung endothelial hydraulic conductivity via nitric oxide/reactive oxygen species. Am. J. Physiol. Lung Cell. Mol. Physiol. 292(6):L1452–L1458, 2007.

    Google Scholar 

  49. Duprez, Daniel A. Arterial stiffness and endothelial function. Hypertension 55(3):612–613, 2010.

    Google Scholar 

  50. Ebong, E. E., S. V. Lopez-Quintero, V. Rizzo, D. C. Spray, and J. M. Tarbell. Shear-induced endothelial NOS activation and remodeling via heparan sulfate, glypican-1, and syndecan-1. Integr Biol (Camb). 6(3):338–347, 2014.

    Google Scholar 

  51. Ebong, E. E., F. P. Macaluso, D. C. Spray, and J. M. Tarbell. Imaging the endothelial glycocalyx in vitro by rapid freezing/freeze substitution transmission electron microscopy. Arterioscler. Thromb. Vasc. Biol. 31(8):1908–1915, 2011.

    Google Scholar 

  52. Erdem, M., S. Erdem, O. Sanli, H. Sak, I. Kilicaslan, F. Sahin, et al. Up-regulation of TGM2 with ITGB1 and SDC4 is important in the development and metastasis of renal cell carcinoma. Urol. Oncol. 32(1):25, 2014.

    Google Scholar 

  53. Eskens, B. J., C. J. Zuurbier, J. van Haare, H. Vink, and J. W. van Teeffelen. Effects of two weeks of metformin treatment on whole-body glycocalyx barrier properties in db/db mice. Cardiovasc. Diabetol. 12:175, 2013.

    Google Scholar 

  54. Estep, R. D., A. N. Govindan, M. Manoharan, H. Li, S. S. Fei, B. S. Park, et al. Molecular analysis of lymphoid tissue from rhesus macaque rhadinovirus-infected monkeys identifies alterations in host genes associated with oncogenesis. PLoS ONE 15(2):e0228484, 2020.

    Google Scholar 

  55. Fan, J., B. Cai, M. Zeng, Y. Hao, F. G. Giancotti, and B. M. Fu. Integrin β4 signaling promotes mammary tumor cell adhesion to brain microvascular endothelium by inducing ErbB2-mediated secretion of VEGF. Ann. Biomed. Eng. 39(8):2223–2241, 2011.

    Google Scholar 

  56. Fan, J., and B. M. Fu. Quantification of malignant breast cancer cell MDA-MB-231 transmigration across brain and lung microvascular endothelium. Ann. Biomed. Eng. 44(7):2189–2201, 2016.

    Google Scholar 

  57. Fan, J., Y. Sun, Y. Xia, J. M. Tarbell, and B. M. Fu. Endothelial surface glycocalyx (ESG) components and ultra-structure revealed by stochastic optical reconstruction microscopy (STORM). Biorheology 56(2–3):77–88, 2019.

    Google Scholar 

  58. Fink, M. P. Animal models of sepsis. Virulence. 5(1):143–153, 2014.

    Google Scholar 

  59. Fleming, I., B. Fisslthaler, M. Dixit, and R. Busse. Role of PECAM-1 in the shear-stress-induced activation of Akt and the endothelial nitric oxide synthase (eNOS) in endothelial cells. J. Cell Sci. 118(Pt 18):4103–4111, 2005.

    Google Scholar 

  60. Florian, J. A., J. R. Kosky, K. Ainslie, Z. Pang, R. O. Dull, and J. M. Tarbell. Heparan sulfate proteoglycan is a mechanosensor on endothelial cells. Circ. Res. 93(10):e136–e142, 2003.

    Google Scholar 

  61. Fu, B. M., and J. M. Tarbell. Mechano-sensing and transduction by endothelial surface glycocalyx: composition, structure, and function. Wiley Interdiscip. Rev. Syst. Biol. Med. 5(3):381–390, 2013.

    Google Scholar 

  62. Gallagher, J. Fell-Muir lecture: heparan sulphate and the art of cell regulation: a polymer chain conducts the protein orchestra. Int. J. Exp. Pathol. 96(4):203–231, 2015.

    Google Scholar 

  63. Goligorsky, M. S., and D. Sun. Glycocalyx in endotoxemia and sepsis. Am. J. Pathol. 190(4):791–798, 2020.

    Google Scholar 

  64. Guerci, P., B. Ergin, Z. Uz, Y. Ince, M. Westphal, M. Heger, et al. Glycocalyx degradation is independent of vascular barrier permeability increase in nontraumatic hemorrhagic shock in rats. Anesth. Analg. 129(2):598–607, 2019.

    Google Scholar 

  65. Guo, W., and F. G. Giancotti. Integrin signalling during tumour progression. Nat. Rev. Mol. Cell Biol. 5(10):816–826, 2004.

    Google Scholar 

  66. Guo, J., Z. C. Yang, and Y. Liu. Attenuating pulmonary hypertension by protecting the integrity of glycocalyx in rats model of pulmonary artery hypertension. Inflammation. 42(6):1951–1956, 2019.

    Google Scholar 

  67. Guo, M., H. Zhang, J. Zheng, and Y. Liu. Glypican-3: a new target for diagnosis and treatment of hepatocellular carcinoma. J. Cancer. 11(8):2008–2021, 2020.

    Google Scholar 

  68. Guyton, H. G., and H. M. Decker. Respiratory protection provided by five new contagion masks. Appl. Microbiol. 11(1):66–68, 1963.

    Google Scholar 

  69. Haeren, R. H., S. E. van de Ven, M. A. van Zandvoort, H. Vink, J. J. van Overbeeke, G. Hoogland, et al. Assessment and imaging of the cerebrovascular glycocalyx. Curr. Neurovasc. Res. 13(3):249–260, 2016.

    Google Scholar 

  70. Haessler, U., J. C. Teo, D. Foretay, P. Renaud, and M. A. Swartz. Migration dynamics of breast cancer cells in a tunable 3D interstitial flow chamber. Integr. Biol. (Camb). 4(4):401–409, 2012.

    Google Scholar 

  71. Hammond, E., A. Khurana, V. Shridhar, and K. Dredge. The role of heparanase and sulfatases in the modification of heparan sulfate proteoglycans within the tumor microenvironment and opportunities for novel cancer therapeutics. Front. Oncol. 4:195, 2014.

    Google Scholar 

  72. Hara, H., T. Takahashi, S. Serada, M. Fujimoto, T. Ohkawara, R. Nakatsuka, et al. Overexpression of glypican-1 implicates poor prognosis and their chemoresistance in oesophageal squamous cell carcinoma. Br. J. Cancer 115(1):66–75, 2016.

    Google Scholar 

  73. Harada, E., S. Serada, M. Fujimoto, Y. Takahashi, T. Takahashi, H. Hara, et al. Glypican-1 targeted antibody-based therapy induces preclinical antitumor activity against esophageal squamous cell carcinoma. Oncotarget. 8(15):24741–24752, 2017.

    Google Scholar 

  74. Harding, I. C., R. Mitra, S. A. Mensah, I. M. Herman, and E. E. Ebong. Pro-atherosclerotic disturbed flow disrupts caveolin-1 expression, localization, and function via glycocalyx degradation. J. Transl. Med. 16(1):364, 2018.

    Google Scholar 

  75. Hempel, C., J. Sporring, and J. A. L. Kurtzhals. Experimental cerebral malaria is associated with profound loss of both glycan and protein components of the endothelial glycocalyx. FASEB J. 33(2):2058–2071, 2019.

    Google Scholar 

  76. Hippensteel, J. A., B. J. Anderson, J. E. Orfila, S. A. McMurtry, R. M. Dietz, G. Su, et al. Circulating heparan sulfate fragments mediate septic cognitive dysfunction. J Clin Invest. 129(4):1779–1784, 2019.

    Google Scholar 

  77. Hu, X., R. H. Adamson, B. Liu, F. E. Curry, and S. Weinbaum. Starling forces that oppose filtration after tissue oncotic pressure is increased. Am. J. Physiol. Heart Circ. Physiol. 279(4):H1724–H1736, 2000.

    Google Scholar 

  78. Hu, X., and S. Weinbaum. A new view of Starling’s hypothesis at the microstructural level. Microvasc. Res. 58(3):281–304, 1999.

    Google Scholar 

  79. Hua, C. T., J. R. Gamble, M. A. Vadas, and D. E. Jackson. Recruitment and activation of SHP-1 protein-tyrosine phosphatase by human platelet endothelial cell adhesion molecule-1 (PECAM-1). Identification of immunoreceptor tyrosine-based inhibitory motif-like binding motifs and substrates. J. Biol. Chem. 273(43):28332–28340, 1998.

    Google Scholar 

  80. Huang, Y., K. M. Jan, D. Rumschitzki, and S. Weinbaum. Structural changes in rat aortic intima due to transmural pressure. J. Biomech. Eng. 120(4):476–483, 1998.

    Google Scholar 

  81. Huang, Y., D. Rumschitzki, S. Chien, and S. Weinbaum. A fiber matrix model for the filtration through fenestral pores in a compressible arterial intima. Am. J. Physiol. 272(4 Pt 2):H2023–H2039, 1997.

    Google Scholar 

  82. Huang, Y. L., C. K. Tung, A. Zheng, B. J. Kim, and M. Wu. Interstitial flows promote amoeboid over mesenchymal motility of breast cancer cells revealed by a three dimensional microfluidic model. Integr. Biol. (Camb). 7(11):1402–1411, 2015.

    Google Scholar 

  83. Ikonomidis, I., G. Pavlidis, J. Thymis, D. Birba, A. Kalogeris, F. Kousathana, et al. Effects of glucagon-like peptide-1 receptor agonists, sodium-glucose cotransporter-2 inhibitors, and their combination on endothelial glycocalyx, arterial function, and myocardial work index in patients with type 2 diabetes mellitus after 12-month treatment. J. Am. Heart Assoc. 9(9):e015716, 2020.

    Google Scholar 

  84. Ikonomidis, I., A. Voumvourakis, G. Makavos, H. Triantafyllidi, G. Pavlidis, K. Katogiannis, et al. Association of impaired endothelial glycocalyx with arterial stiffness, coronary microcirculatory dysfunction, and abnormal myocardial deformation in untreated hypertensives. J. Clin. Hypertens. (Greenwich). 20(4):672–679, 2018.

    Google Scholar 

  85. Introini, V., A. Carciati, G. Tomaiuolo, P. Cicuta, and S. Guido. Endothelial glycocalyx regulates cytoadherence in Plasmodium falciparum malaria. J. R. Soc. Interface 15(149):20180773, 2018.

    Google Scholar 

  86. Iozzo, R. V., and R. D. Sanderson. Proteoglycans in cancer biology, tumour microenvironment and angiogenesis. J. Cell Mol. Med. 15(5):1013–1031, 2011.

    Google Scholar 

  87. Jagannath, S., L. T. Heffner, Jr, S. Ailawadhi, N. C. Munshi, T. M. Zimmerman, J. Rosenblatt, et al. Indatuximab ravtansine (BT062) monotherapy in patients with relapsed and/or refractory multiple myeloma. Clin. Lymphoma Myeloma Leuk. 19(6):372–380, 2019.

    Google Scholar 

  88. Jia, L., and S. Ma. Recent advances in the discovery of heparanase inhibitors as anti-cancer agents. Eur. J. Med. Chem. 121:209–220, 2016.

    Google Scholar 

  89. Jian, Y. S., C. W. Chen, C. A. Lin, H. P. Yu, H. Y. Lin, M. Y. Liao, et al. Hyaluronic acid-nimesulide conjugates as anticancer drugs against CD44-overexpressing HT-29 colorectal cancer in vitro and in vivo. Int. J. Nanomed. 12:2315–2333, 2017.

    Google Scholar 

  90. Johansson, P. I., J. Stensballe, L. S. Rasmussen, and S. R. Ostrowski. A high admission syndecan-1 level, a marker of endothelial glycocalyx degradation, is associated with inflammation, protein C depletion, fibrinolysis, and increased mortality in trauma patients. Ann. Surg. 254(2):194–200, 2011.

    Google Scholar 

  91. Jung, O., V. Trapp-Stamborski, A. Purushothaman, H. Jin, H. Wang, R. D. Sanderson, et al. Heparanase-induced shedding of syndecan-1/CD138 in myeloma and endothelial cells activates VEGFR2 and an invasive phenotype: prevention by novel synstatins. Oncogenesis. 5:e202, 2016.

    Google Scholar 

  92. Karousou, E., S. Misra, S. Ghatak, K. Dobra, M. Gotte, D. Vigetti, et al. Roles and targeting of the HAS/hyaluronan/CD44 molecular system in cancer. Matrix Biol. 59:3–22, 2017.

    Google Scholar 

  93. Kazuma, S., Y. Tokinaga, M. Kimizuka, R. Azumaguchi, K. Hamada, and M. Yamakage. Sevoflurane promotes regeneration of the endothelial glycocalyx by upregulating sialyltransferase. J. Surg. Res. 241:40–47, 2019.

    Google Scholar 

  94. Kim, Y. H., P. Nijst, K. Kiefer, and W. H. Tang. Endothelial glycocalyx as biomarker for cardiovascular diseases: mechanistic and clinical implications. Curr. Heart Fail. Rep. 14(2):117–126, 2017.

    Google Scholar 

  95. Kind, S., C. Merenkow, F. Buscheck, K. Moller, D. Dum, V. Chirico, et al. Prevalence of Syndecan-1 (CD138) expression in different kinds of human tumors and normal tissues. Dis. Markers 2019:4928315, 2019.

    Google Scholar 

  96. Kingsmore, K. M., D. K. Logsdon, D. H. Floyd, S. M. Peirce, B. W. Purow, and J. M. Munson. Interstitial flow differentially increases patient-derived glioblastoma stem cell invasion via CXCR4, CXCL12, and CD44-mediated mechanisms. Integr. Biol. (Camb). 8(12):1246–1260, 2016.

    Google Scholar 

  97. Kleeff, J., T. Ishiwata, A. Kumbasar, H. Friess, M. W. Buchler, A. D. Lander, et al. The cell-surface heparan sulfate proteoglycan glypican-1 regulates growth factor action in pancreatic carcinoma cells and is overexpressed in human pancreatic cancer. J. Clin. Invest. 102(9):1662–1673, 1998.

    Google Scholar 

  98. Kuchan, M. J., and J. A. Frangos. Role of calcium and calmodulin in flow-induced nitric oxide production in endothelial cells. Am. J. Physiol. 266(3 Pt 1):C628–C636, 1994.

    Google Scholar 

  99. Kumase, F., Y. Morizane, S. Mohri, I. Takasu, A. Ohtsuka, and H. Ohtsuki. Glycocalyx degradation in retinal and choroidal capillary endothelium in rats with diabetes and hypertension. Acta Med. Okayama 64(5):277–283, 2010.

    Google Scholar 

  100. Kusche-Vihrog, K., and H. Oberleithner. An emerging concept of vascular salt sensitivity. Biol. Rep. 4:20, 2012.

    Google Scholar 

  101. Landis, H. R. Laboratory and clinical methods. Trans. Am. Climatol. Clin. Assoc. 43:134–143, 1927.

    Google Scholar 

  102. Landman, G. W., N. Kleefstra, K. J. van Hateren, K. H. Groenier, R. O. Gans, and H. J. Bilo. Metformin associated with lower cancer mortality in type 2 diabetes: ZODIAC-16. Diabetes Care 33(2):322–326, 2010.

    Google Scholar 

  103. Lang, J., N. Yang, J. Deng, K. Liu, P. Yang, G. Zhang, et al. Inhibition of SARS pseudovirus cell entry by lactoferrin binding to heparan sulfate proteoglycans. PLoS ONE 6(8):e23710, 2011.

    Google Scholar 

  104. Lanzi, C., and G. Cassinelli. Heparan sulfate mimetics in cancer therapy: the challenge to define structural determinants and the relevance of targets for optimal activity. Molecules. 23(11):2915, 2018.

    Google Scholar 

  105. Lauster, D., M. Glanz, M. Bardua, K. Ludwig, M. Hellmund, U. Hoffmann, et al. Multivalent peptide-nanoparticle conjugates for influenza-virus inhibition. Angew. Chem. Int. Ed. Engl. 56(21):5931–5936, 2017.

    Google Scholar 

  106. Leskova, W., H. Pickett, R. S. Eshaq, B. Shrestha, C. B. Pattillo, and N. R. Harris. Effect of diabetes and hyaluronidase on the retinal endothelial glycocalyx in mice. Exp. Eye Res. 179:125–131, 2019.

    Google Scholar 

  107. Levick, J. R. Capillary filtration-absorption balance reconsidered in light of dynamic extravascular factors. Exp. Physiol. 76(6):825–857, 1991.

    Google Scholar 

  108. Levick, J. R., and C. C. Michel. Microvascular fluid exchange and the revised Starling principle. Cardiovasc. Res. 87(2):198–210, 2010.

    Google Scholar 

  109. Lewis, J. C., R. G. Taylor, N. D. Jones, R. W. St Clair, and J. F. Cornhill. Endothelial surface characteristics in pigeon coronary artery atherosclerosis. I. Cellular alterations during the initial stages of dietary cholesterol challenge. Lab Invest. 46(2):123–138, 1982.

    Google Scholar 

  110. Li, J., Y. Chen, X. Guo, L. Zhou, Z. Jia, Z. Peng, et al. GPC1 exosome and its regulatory miRNAs are specific markers for the detection and target therapy of colorectal cancer. J. Cell Mol. Med. 21(5):838–847, 2017.

    Google Scholar 

  111. Li, J., B. Li, C. Ren, Y. Chen, X. Guo, L. Zhou, et al. The clinical significance of circulating GPC1 positive exosomes and its regulative miRNAs in colon cancer patients. Oncotarget. 8(60):101189–101202, 2017.

    Google Scholar 

  112. Li, T., X. Liu, Z. Zhao, L. Ni, and C. Liu. Sulodexide recovers endothelial function through reconstructing glycocalyx in the balloon-injury rat carotid artery model. Oncotarget. 8(53):91350–91361, 2017.

    Google Scholar 

  113. Li, J., T. Yuan, X. Zhao, G. Y. Lv, and H. Q. Liu. Protective effects of sevoflurane in hepatic ischemia-reperfusion injury. Int. J. Immunopathol. Pharmacol. 29(2):300–307, 2016.

    Google Scholar 

  114. Ligi, D., L. Croce, and F. Mannello. Chronic venous disorders: the dangerous, the good, and the diverse. Int. J. Mol. Sci. 19(9):2544, 2018.

    Google Scholar 

  115. Lim, H. C., and J. R. Couchman. Syndecan-2 regulation of morphology in breast carcinoma cells is dependent on RhoGTPases. Biochim. Biophys. Acta 1840(8):2482–2490, 2014.

    Google Scholar 

  116. Lopez-Quintero, S. V., L. M. Cancel, A. Pierides, D. Antonetti, D. C. Spray, and J. M. Tarbell. High glucose attenuates shear-induced changes in endothelial hydraulic conductivity by degrading the glycocalyx. PLoS ONE 8(11):e78954, 2013.

    Google Scholar 

  117. Lu, H., F. Niu, F. Liu, J. Gao, Y. Sun, and X. Zhao. Elevated glypican-1 expression is associated with an unfavorable prognosis in pancreatic ductal adenocarcinoma. Cancer Med. 6(6):1181–1191, 2017.

    Google Scholar 

  118. Lygizos, M. I., Y. Yang, C. J. Altmann, K. Okamura, A. A. Hernando, M. J. Perez, et al. Heparanase mediates renal dysfunction during early sepsis in mice. Physiol. Rep. 1(6):e00153, 2013.

    Google Scholar 

  119. Machin, D. R., S. I. Bloom, R. A. Campbell, T. T. T. Phuong, P. E. Gates, L. A. Lesniewski, et al. Advanced age results in a diminished endothelial glycocalyx. Am. J. Physiol. Heart Circ. Physiol. 315(3):H531–H539, 2018.

    Google Scholar 

  120. Mahmoud, M., M. Mayer, L. M. Cancel, A. M. Bartosch, R. Mathews, and J. M. Tarbell. The Glycocalyx core protein Glypican 1 protects vessel wall endothelial cells from stiffness-mediated dysfunction and disease. Cardiovasc. Res. 20:10, 2020. https://doi.org/10.1093/cvr/cvaa201.

    Article  Google Scholar 

  121. Majerczak, J., K. Duda, S. Chlopicki, G. Bartosz, A. Zakrzewska, A. Balcerczyk, et al. Endothelial glycocalyx integrity is preserved in young, healthy men during a single bout of strenuous physical exercise. Physiol. Res. 65(2):281–291, 2016.

    Google Scholar 

  122. Majerczak, J., M. Grandys, K. Duda, A. Zakrzewska, A. Balcerczyk, L. Kolodziejski, et al. Moderate-intensity endurance training improves endothelial glycocalyx layer integrity in healthy young men. Exp. Physiol. 102(1):70–85, 2017.

    Google Scholar 

  123. Mansilha, A., and J. Sousa. Pathophysiological mechanisms of chronic venous disease and implications for venoactive drug therapy. Int. J. Mol. Sci. 19(6):1669, 2018.

    Google Scholar 

  124. Maruhashi, T., J. Soga, N. Fujimura, N. Idei, S. Mikami, Y. Iwamoto, et al. Endothelial dysfunction, increased arterial stiffness, and cardiovascular risk prediction in patients with coronary artery disease: FMD-J (Flow-Mediated Dilation Japan) Study A. J. Am. Heart Assoc. 7(14):e008588, 2018.

    Google Scholar 

  125. Masuda, M., M. Osawa, H. Shigematsu, N. Harada, and K. Fujiwara. Platelet endothelial cell adhesion molecule-1 is a major SH-PTP2 binding protein in vascular endothelial cells. FEBS Lett. 408(3):331–336, 1997.

    Google Scholar 

  126. Matsuda, K., H. Maruyama, F. Guo, J. Kleeff, J. Itakura, Y. Matsumoto, et al. Glypican-1 is overexpressed in human breast cancer and modulates the mitogenic effects of multiple heparin-binding growth factors in breast cancer cells. Cancer Res. 61(14):5562–5569, 2001.

    Google Scholar 

  127. Matsuzaki, S., S. Serada, K. Hiramatsu, S. Nojima, Y. Ueda, T. Ohkawara, et al. Anti-glypican-1 antibody-drug conjugate exhibits potent preclinical antitumor activity against glypican-1 positive uterine cervical cancer. Int. J. Cancer 142(5):1056–1066, 2018.

    Google Scholar 

  128. Matthay, M. A., R. L. Zemans, G. A. Zimmerman, Y. M. Arabi, J. R. Beitler, A. Mercat, et al. Acute respiratory distress syndrome. Nat. Rev. Dis. Primers. 5(1):18, 2019.

    Google Scholar 

  129. McGarrity, S., Ó. Anuforo, H. Halldórsson, A. Bergmann, S. Halldórsson, S. Palsson, et al. Metabolic systems analysis of LPS induced endothelial dysfunction applied to sepsis patient stratification. Sci. Rep. 8(1):6811, 2018.

    Google Scholar 

  130. Mele, V., L. Sokol, V. H. Kolzer, D. Pfaff, M. G. Muraro, I. Keller, et al. The hyaluronan-mediated motility receptor RHAMM promotes growth, invasiveness and dissemination of colorectal cancer. Oncotarget. 8(41):70617–70629, 2017.

    Google Scholar 

  131. Melo, S. A., L. B. Luecke, C. Kahlert, A. F. Fernandez, S. T. Gammon, J. Kaye, et al. Glypican-1 identifies cancer exosomes and detects early pancreatic cancer. Nature 523(7559):177–182, 2015.

    Google Scholar 

  132. Mensah, S. A., M. J. Cheng, H. Homayoni, B. D. Plouffe, A. J. Coury, and E. E. Ebong. Regeneration of glycocalyx by heparan sulfate and sphingosine 1-phosphate restores inter-endothelial communication. PLoS ONE 12(10):e0186116, 2017.

    Google Scholar 

  133. Michel, C. C. Fluid movement through capillary walls. Handbook of Physiology: Sect 2. Philadelphia: American Physiological Society, 1984.

  134. Michel, C. C. Starling: the formulation of his hypothesis of microvascular fluid exchange and its significance after 100 years. Exp. Physiol. 82(1):1–30, 1997.

    Google Scholar 

  135. Michel, C. C., and M. E. Phillips. Steady-state fluid filtration at different capillary pressures in perfused frog mesenteric capillaries. J. Physiol. 388:421–435, 1987.

    Google Scholar 

  136. Milewska, A., M. Zarebski, P. Nowak, K. Stozek, J. Potempa, and K. Pyrc. Human coronavirus NL63 utilizes heparan sulfate proteoglycans for attachment to target cells. J. Virol. 88(22):13221–13230, 2014.

    Google Scholar 

  137. Mishra, H. K., J. Ma, and B. Walcheck. Ectodomain Shedding by ADAM17: its role in neutrophil recruitment and the impairment of this process during sepsis. Front Cell Infect. Microbiol. 7:138, 2017.

    Google Scholar 

  138. Misra, S., V. C. Hascall, R. R. Markwald, and S. Ghatak. Interactions between Hyaluronan and Its Receptors (CD44, RHAMM) Regulate the Activities of Inflammation and Cancer. Front Immunol. 6:201, 2015.

    Google Scholar 

  139. Misra, S., P. Heldin, V. C. Hascall, N. K. Karamanos, S. S. Skandalis, R. R. Markwald, et al. Hyaluronan-CD44 interactions as potential targets for cancer therapy. FEBS J. 278(9):1429–1443, 2011.

    Google Scholar 

  140. Mitchell, G. F. Arterial stiffness and hypertension: chicken or egg? Hypertension 64(2):210–214, 2014.

    Google Scholar 

  141. Mitchell, G. F., S.-J. Hwang, R. S. Vasan, M. G. Larson, M. J. Pencina, N. M. Hamburg, et al. Arterial stiffness and cardiovascular events: the Framingham Heart Study. Circulation 121(4):505–511, 2010.

    Google Scholar 

  142. Moran, H., L. M. Cancel, M. A. Mayer, H. Qazi, L. L. Munn, and J. M. Tarbell. The cancer cell glycocalyx proteoglycan Glypican-1 mediates interstitial flow mechanotransduction to enhance cell migration and metastasis. Biorheology 56(2–3):151–161, 2019.

    Google Scholar 

  143. Munkley, J., and D. J. Elliott. Hallmarks of glycosylation in cancer. Oncotarget. 7(23):35478–35489, 2016.

    Google Scholar 

  144. Munkley, J., and E. Scott. Targeting aberrant sialylation to treat cancer. Medicines (Basel). 6(4):102, 2019.

    Google Scholar 

  145. Munson, J. M., R. V. Bellamkonda, and M. A. Swartz. Interstitial flow in a 3D microenvironment increases glioma invasion by a CXCR4-dependent mechanism. Cancer Res. 73(5):1536–1546, 2013.

    Google Scholar 

  146. Munson, J. M., and A. C. Shieh. Interstitial fluid flow in cancer: implications for disease progression and treatment. Cancer Manag. Res. 6:317–328, 2014.

    Google Scholar 

  147. Nägga, K., O. Hansson, D. van Westen, L. Minthon, and M. Wennström. Increased levels of hyaluronic acid in cerebrospinal fluid in patients with vascular dementia. J. Alzheimers Dis. 42(4):1435–1441, 2014.

    Google Scholar 

  148. Nagy, N., T. Freudenberger, A. Melchior-Becker, K. Röck, M. Ter Braak, H. Jastrow, et al. Inhibition of hyaluronan synthesis accelerates murine atherosclerosis: novel insights into the role of hyaluronan synthesis. Circulation 122(22):2313–2322, 2010.

    Google Scholar 

  149. Nelson, A., I. Berkestedt, and M. Bodelsson. Circulating glycosaminoglycan species in septic shock. Acta Anaesthesiol. Scand. 58(1):36–43, 2014.

    Google Scholar 

  150. Neves, F. M., G. C. Meneses, N. E. Sousa, R. R. Menezes, M. C. Parahyba, A. M. Martins, et al. Syndecan-1 in acute decompensated heart failure-association with renal function and mortality. Circ. J. 79(7):1511–1519, 2015.

    Google Scholar 

  151. Nieuwdorp, M., M. C. Meuwese, H. L. Mooij, M. H. van Lieshout, A. Hayden, M. Levi, et al. Tumor necrosis factor-alpha inhibition protects against endotoxin-induced endothelial glycocalyx perturbation. Atherosclerosis. 202(1):296–303, 2009.

    Google Scholar 

  152. Nijst, P., J. Cops, P. Martens, Q. Swennen, M. Dupont, W. H. W. Tang, et al. Endovascular shedding markers in patients with heart failure with reduced ejection fraction: results from a single-center exploratory study. Microcirculation. 25:2, 2018. https://doi.org/10.3390/jcm7110400.

    Article  Google Scholar 

  153. Nishida, T., and H. Kataoka. Glypican 3-targeted therapy in hepatocellular carcinoma. Cancers (Basel). 11(9):1339, 2019.

    Google Scholar 

  154. Nishigaki, T., T. Takahashi, S. Serada, M. Fujimoto, T. Ohkawara, H. Hara, et al. Anti-glypican-1 antibody-drug conjugate is a potential therapy against pancreatic cancer. Br. J. Cancer 122(9):1333–1341, 2020.

    Google Scholar 

  155. Oberleithner, H. Vascular endothelium: a vulnerable transit zone for merciless sodium. Nephrol. Dial. Transplant. 29(2):240–246, 2014.

    Google Scholar 

  156. Okamoto, T., N. Akita, M. Terasawa, T. Hayashi, and K. Suzuki. Rhamnan sulfate extracted from Monostroma nitidum attenuates blood coagulation and inflammation of vascular endothelial cells. J. Nat. Med. 73(3):614–619, 2019.

    Google Scholar 

  157. Osawa, M., M. Masuda, N. Harada, R. B. Lopes, and K. Fujiwara. Tyrosine phosphorylation of platelet endothelial cell adhesion molecule-1 (PECAM-1, CD31) in mechanically stimulated vascular endothelial cells. Eur. J. Cell Biol. 72(3):229–237, 1997.

    Google Scholar 

  158. Padberg, J. S., A. Wiesinger, G. S. di Marco, S. Reuter, A. Grabner, D. Kentrup, et al. Damage of the endothelial glycocalyx in chronic kidney disease. Atherosclerosis. 234(2):335–343, 2014.

    Google Scholar 

  159. Pahakis, M. Y., J. R. Kosky, R. O. Dull, and J. M. Tarbell. The role of endothelial glycocalyx components in mechanotransduction of fluid shear stress. Biochem. Biophys. Res. Commun. 355(1):228–233, 2007.

    Google Scholar 

  160. Pang, Z., and J. M. Tarbell. In vitro study of Starling’s hypothesis in a cultured monolayer of bovine aortic endothelial cells. J. Vasc. Res. 40(4):351–358, 2003.

    Google Scholar 

  161. Pappenheimer, J. R., and A. Soto-Rivera. Effective osmotic pressure of the plasma proteins and other quantities associated with the capillary circulation in the hindlimbs of cats and dogs. Am. J. Physiol. 152(3):471–491, 1948.

    Google Scholar 

  162. Park, H., Y. Kim, Y. Lim, I. Han, and E. S. Oh. Syndecan-2 mediates adhesion and proliferation of colon carcinoma cells. J. Biol. Chem. 277(33):29730–29736, 2002.

    Google Scholar 

  163. Paszek, M. J., C. C. DuFort, O. Rossier, R. Bainer, J. K. Mouw, K. Godula, et al. The cancer glycocalyx mechanically primes integrin-mediated growth and survival. Nature 511(7509):319–325, 2014.

    Google Scholar 

  164. Pisano, C., I. Vlodavsky, N. Ilan, and F. Zunino. The potential of heparanase as a therapeutic target in cancer. Biochem. Pharmacol. 89(1):12–19, 2014.

    Google Scholar 

  165. Piva, S., V. A. McCreadie, and N. Latronico. Neuroinflammation in sepsis: sepsis associated delirium. Cardiovasc. Hematol. Disord.: Drug Targets 15(1):10–18, 2015.

    Google Scholar 

  166. Polikarpov, D., L. Liang, A. Care, A. Sunna, D. Campbell, B. Walsh, et al. Functionalized upconversion nanoparticles for targeted labelling of bladder cancer cells. Biomolecules. 9(12):820, 2019.

    Google Scholar 

  167. Puerta-Guardo, H., D. R. Glasner, D. A. Espinosa, S. B. Biering, M. Patana, K. Ratnasiri, et al. Flavivirus NS1 triggers tissue-specific vascular endothelial dysfunction reflecting disease tropism. Cell Rep. 26(6):1598–1613, 2019.

    Google Scholar 

  168. Puerta-Guardo, H., D. R. Glasner, and E. Harris. Dengue virus NS1 disrupts the endothelial glycocalyx, leading to hyperpermeability. PLoS Pathog. 12(7):e1005738, 2016.

    Google Scholar 

  169. Qazi, H., R. Palomino, Z. D. Shi, L. L. Munn, and J. M. Tarbell. Cancer cell glycocalyx mediates mechanotransduction and flow-regulated invasion. Integr. Biol. (Camb). 5(11):1334–1343, 2013.

    Google Scholar 

  170. Qazi, H., Z. D. Shi, J. W. Song, L. M. Cancel, P. Huang, Y. Zeng, et al. Heparan sulfate proteoglycans mediate renal carcinoma metastasis. Int. J. Cancer 139(12):2791–2801, 2016.

    Google Scholar 

  171. Qazi, H., Z. D. Shi, and J. M. Tarbell. Fluid shear stress regulates the invasive potential of glioma cells via modulation of migratory activity and matrix metalloproteinase expression. PLoS ONE 6(5):e20348, 2011.

    Google Scholar 

  172. Rai, S., Z. Nejadhamzeeigilani, N. J. Gutowski, and J. L. Whatmore. Loss of the endothelial glycocalyx is associated with increased E-selectin mediated adhesion of lung tumour cells to the brain microvascular endothelium. J. Exp. Clin. Cancer Res. 34:105, 2015.

    Google Scholar 

  173. Ramnath, R., R. R. Foster, Y. Qiu, G. Cope, M. J. Butler, A. H. Salmon, et al. Matrix metalloproteinase 9-mediated shedding of syndecan 4 in response to tumor necrosis factor α: a contributor to endothelial cell glycocalyx dysfunction. FASEB J. 28(11):4686–4699, 2014.

    Google Scholar 

  174. Reyes-Soffer, G., S. Holleran, M. R. Di Tullio, S. Homma, B. Boden-Albala, R. Ramakrishnan, et al. Endothelial function in individuals with coronary artery disease with and without type 2 diabetes mellitus. Metabolism. 59(9):1365–1371, 2010.

    Google Scholar 

  175. Richter, V., M. D. Savery, M. Gassmann, O. Baum, E. R. Damiano, and A. R. Pries. Excessive erythrocytosis compromises the blood-endothelium interface in erythropoietin-overexpressing mice. J. Physiol. 589(Pt 21):5181–5192, 2011.

    Google Scholar 

  176. Russell-Puleri, S., N. G. Dela Paz, D. Adams, M. Chattopadhyay, L. Cancel, E. Ebong, et al. Fluid shear stress induces upregulation of COX-2 and PGI(2) release in endothelial cells via a pathway involving PECAM-1, PI3K, FAK, and p38. Am. J. Physiol. Heart Circ. Physiol. 312(3):H485–H500, 2017.

    Google Scholar 

  177. Rzhevskiy, A. S., S. Razavi Bazaz, L. Ding, A. Kapitannikova, N. Sayyadi, D. Campbell, et al. Rapid and label-free isolation of tumour cells from the urine of patients with localised prostate cancer using inertial microfluidics. Cancers (Basel). 12(1):81, 2019.

    Google Scholar 

  178. Saito, T., K. Sugiyama, S. Hama, F. Yamasaki, T. Takayasu, R. Nosaka, et al. High expression of glypican-1 predicts dissemination and poor prognosis in glioblastomas. World Neurosurg. 105:282–288, 2017.

    Google Scholar 

  179. Salmon, A. H., J. K. Ferguson, J. L. Burford, H. Gevorgyan, D. Nakano, S. J. Harper, et al. Loss of the endothelial glycocalyx links albuminuria and vascular dysfunction. J. Am. Soc. Nephrol. 23(8):1339–1350, 2012.

    Google Scholar 

  180. Sardu, C., J. Gambardella, M. B. Morelli, X. Wang, R. Marfella, and G. Santulli. Hypertension, thrombosis, kidney failure, and diabetes: is COVID-19 an endothelial disease? A comprehensive evaluation of clinical and basic evidence. J. Clin. Med. 9(5):1417, 2020.

    Google Scholar 

  181. Schierke, F., M. J. Wyrwoll, M. Wisdorf, L. Niedzielski, M. Maase, T. Ruck, et al. Nanomechanics of the endothelial glycocalyx contribute to Na(+)-induced vascular inflammation. Sci. Rep. 7:46476, 2017.

    Google Scholar 

  182. Schmidt, E. P., Y. Yang, W. J. Janssen, A. Gandjeva, M. J. Perez, L. Barthel, et al. The pulmonary endothelial glycocalyx regulates neutrophil adhesion and lung injury during experimental sepsis. Nat. Med. 18(8):1217–1223, 2012.

    Google Scholar 

  183. Schmitz, B., H. Niehues, M. Lenders, L. Thorwesten, A. Klose, M. Krüger, et al. Effects of high-intensity interval training on microvascular glycocalyx and associated microRNAs. Am. J. Physiol. Heart Circ. Physiol. 316(6):H1538–H1551, 2019.

    Google Scholar 

  184. Schonfeld, K., P. Herbener, C. Zuber, T. Hader, K. Bernoster, C. Uherek, et al. Activity of indatuximab ravtansine against triple-negative breast cancer in preclinical tumor models. Pharm. Res. 35(6):118, 2018.

    Google Scholar 

  185. Secomb, T. W., R. Hsu, and A. R. Pries. Effect of the endothelial surface layer on transmission of fluid shear stress to endothelial cells. Biorheology 38(2–3):143–150, 2001.

    Google Scholar 

  186. Sehba, F. A., W. H. Ding, I. Chereshnev, and J. B. Bederson. Effects of S-nitrosoglutathione on acute vasoconstriction and glutamate release after subarachnoid hemorrhage. Stroke 30(9):1955–1961, 1999.

    Google Scholar 

  187. Shen, S., J. Fan, B. Cai, Y. Lv, M. Zeng, Y. Hao, et al. Vascular endothelial growth factor enhances cancer cell adhesion to microvascular endothelium in vivo. Exp. Physiol. 95(2):369–379, 2010.

    Google Scholar 

  188. Shields, J. D., M. E. Fleury, C. Yong, A. A. Tomei, G. J. Randolph, and M. A. Swartz. Autologous chemotaxis as a mechanism of tumor cell homing to lymphatics via interstitial flow and autocrine CCR7 signaling. Cancer Cell 11(6):526–538, 2007.

    Google Scholar 

  189. Shinyo, Y., J. Kodama, T. Hasengaowa, T. Kusumoto, and Y. Hiramatsu. Loss of cell-surface heparan sulfate expression in both cervical intraepithelial neoplasm and invasive cervical cancer. Gynecol. Oncol. 96(3):776–783, 2005.

    Google Scholar 

  190. Simizu, S., K. Ishida, and H. Osada. Heparanase as a molecular target of cancer chemotherapy. Cancer Sci. 95(7):553–558, 2004.

    Google Scholar 

  191. Soares, M. A., F. C. Teixeira, M. Fontes, A. L. Areas, M. G. Leal, M. S. Pavao, et al. Heparan sulfate proteoglycans may promote or inhibit cancer progression by interacting with integrins and affecting cell migration. Biomed. Res. Int. 2015:453801, 2015.

    Google Scholar 

  192. Son, D. J., S. Kumar, W. Takabe, C. W. Kim, C. W. Ni, N. Alberts-Grill, et al. The atypical mechanosensitive microRNA-712 derived from pre-ribosomal RNA induces endothelial inflammation and atherosclerosis. Nat. Commun. 4:3000, 2013.

    Google Scholar 

  193. Song, J. W., and M. S. Goligorsky. Perioperative implication of the endothelial glycocalyx. Korean J. Anesthesiol. 71(2):92–102, 2018.

    Google Scholar 

  194. Song, J. W., J. A. Zullo, D. Liveris, M. Dragovich, X. F. Zhang, and M. S. Goligorsky. Therapeutic restoration of endothelial glycocalyx in sepsis. J. Pharmacol. Exp. Ther. 361(1):115–121, 2017.

    Google Scholar 

  195. Starling, E. H. On the absorption of fluids from the connective tissue spaces. J. Physiol. 19(4):312–326, 1896.

    Google Scholar 

  196. Suwarto, S., R. T. Sasmono, R. Sinto, E. Ibrahim, and M. Suryamin. Association of endothelial glycocalyx and tight and adherens junctions with severity of plasma leakage in dengue infection. J. Infect. Dis. 215(6):992–999, 2017.

    Google Scholar 

  197. Suzuki, K., and M. Terasawa. Biological activities of rhamnan sulfate extract from the green algae Monostroma nitidum (Hitoegusa). Mar. Drugs. 18(4):228, 2020.

    Google Scholar 

  198. Tammi, R. H., A. Kultti, V. M. Kosma, R. Pirinen, P. Auvinen, and M. I. Tammi. Hyaluronan in human tumors: pathobiological and prognostic messages from cell-associated and stromal hyaluronan. Semin. Cancer Biol. 18(4):288–295, 2008.

    Google Scholar 

  199. Tang, T. H., S. Alonso, L. F. Ng, T. L. Thein, V. J. Pang, Y. S. Leo, et al. Increased serum hyaluronic acid and heparan sulfate in dengue fever: association with plasma leakage and disease severity. Sci. Rep. 7:46191, 2017.

    Google Scholar 

  200. Tarbell, J. M., and L. M. Cancel. The glycocalyx and its significance in human medicine. J. Intern. Med. 280(1):97–113, 2016.

    Google Scholar 

  201. Tarbell, J. M., and E. E. Ebong. The endothelial glycocalyx: a mechano-sensor and -transducer. Sci. Signal. 1(40):8, 2008.

    Google Scholar 

  202. Tarbell, J. M., and M. Y. Pahakis. Mechanotransduction and the glycocalyx. J. Intern. Med. 259(4):339–350, 2006.

    Google Scholar 

  203. Targosz-Korecka, M., M. Jaglarz, K. E. Malek-Zietek, A. Gregorius, A. Zakrzewska, B. Sitek, et al. AFM-based detection of glycocalyx degradation and endothelial stiffening in the db/db mouse model of diabetes. Sci. Rep. 7(1):15951, 2017.

    Google Scholar 

  204. Targosz-Korecka, M., K. E. Malek-Zietek, D. Kloska, Z. Rajfur, E. L. Stepien, A. Grochot-Przeczek, et al. Metformin attenuates adhesion between cancer and endothelial cells in chronic hyperglycemia by recovery of the endothelial glycocalyx barrier. Biochim. Biophys. Acta Gen. Subj. 1864(4):129533, 2020.

    Google Scholar 

  205. Thi, M. M., J. M. Tarbell, S. Weinbaum, and D. C. Spray. The role of the glycocalyx in reorganization of the actin cytoskeleton under fluid shear stress: a “bumper-car” model. Proc. Natl. Acad. Sci. USA. 101(47):16483–16488, 2004.

    Google Scholar 

  206. Torres Filho, I. P., L. N. Torres, C. Salgado, and M. A. Dubick. Novel adjunct drugs reverse endothelial glycocalyx damage after hemorrhagic shock in rats. Shock. 48(5):583–589, 2017.

    Google Scholar 

  207. Tuma, M., S. Canestrini, Z. Alwahab, and J. Marshall. Trauma and endothelial glycocalyx: the microcirculation helmet? Shock. 46(4):352–357, 2016.

    Google Scholar 

  208. Tzima, E., M. Irani-Tehrani, W. B. Kiosses, E. Dejana, D. A. Schultz, B. Engelhardt, et al. A mechanosensory complex that mediates the endothelial cell response to fluid shear stress. Nature 437(7057):426–431, 2005.

    Google Scholar 

  209. Uchimido, R., E. P. Schmidt, and N. I. Shapiro. The glycocalyx: a novel diagnostic and therapeutic target in sepsis. Crit. Care 23(1):16, 2019.

    Google Scholar 

  210. Ueno, M., H. Sakamoto, Y. J. Liao, M. Onodera, C. L. Huang, H. Miyanaka, et al. Blood-brain barrier disruption in the hypothalamus of young adult spontaneously hypertensive rats. Histochem. Cell Biol. 122(2):131–137, 2004.

    Google Scholar 

  211. Ueno, M., H. Sakamoto, H. Tomimoto, I. Akiguchi, M. Onodera, C. L. Huang, et al. Blood-brain barrier is impaired in the hippocampus of young adult spontaneously hypertensive rats. Acta Neuropathol. 107(6):532–538, 2004.

    Google Scholar 

  212. van den Berg, B. M., J. A. Spaan, T. M. Rolf, and H. Vink. Atherogenic region and diet diminish glycocalyx dimension and increase intima-to-media ratios at murine carotid artery bifurcation. Am. J. Physiol. Heart. Circ. Physiol. 290(2):H915–H920, 2006.

    Google Scholar 

  213. van den Berg, B. M., J. A. Spaan, and H. Vink. Impaired glycocalyx barrier properties contribute to enhanced intimal low-density lipoprotein accumulation at the carotid artery bifurcation in mice. Pflugers Arch. 457(6):1199–1206, 2009.

    Google Scholar 

  214. van Haare, J., M. E. Kooi, J. W. van Teeffelen, H. Vink, J. Slenter, H. Cobelens, et al. Metformin and sulodexide restore cardiac microvascular perfusion capacity in diet-induced obese rats. Cardiovasc. Diabetol. 16(1):47, 2017.

    Google Scholar 

  215. Van Wyngene, L., J. Vandewalle, and C. Libert. Reprogramming of basic metabolic pathways in microbial sepsis: therapeutic targets at last. EMBO Mol. Med. 10(8):7812, 2018.

    Google Scholar 

  216. Vlahu, C. A., B. A. Lemkes, D. G. Struijk, M. G. Koopman, R. T. Krediet, and H. Vink. Damage of the endothelial glycocalyx in dialysis patients. J. Am. Soc. Nephrol. 23(11):1900–1908, 2012.

    Google Scholar 

  217. Wagenseil, J. E., and R. P. Mecham. Elastin in large artery stiffness and hypertension. J. Cardiovasc. Transl. Res. 5(3):264–273, 2012.

    Google Scholar 

  218. Wang, S., Y. Qiu, and B. Bai. The expression, regulation, and biomarker potential of glypican-1 in cancer. Front. Oncol. 9:614, 2019.

    Google Scholar 

  219. Weinbaum, S. 1997 Whitaker distinguished lecture: models to solve mysteries in biomechanics at the cellular level; a new view of fiber matrix layers. Ann. Biomed. Eng. 26(4):627–643, 1998.

    Google Scholar 

  220. Weinbaum, S., J. M. Tarbell, and E. R. Damiano. The structure and function of the endothelial glycocalyx layer. Annu. Rev. Biomed. Eng. 9:121–167, 2007.

    Google Scholar 

  221. Weinbaum, S., X. Zhang, Y. Han, H. Vink, and S. C. Cowin. Mechanotransduction and flow across the endothelial glycocalyx. Proc. Natl. Acad. Sci. USA. 100(13):7988–7995, 2003.

    Google Scholar 

  222. Weissgerber, T. L., O. Garcia-Valencia, N. M. Milic, E. Codsi, H. Cubro, M. C. Nath, et al. Early onset preeclampsia is associated with glycocalyx degradation and reduced microvascular perfusion. J. Am. Heart Assoc. 8(4):e010647, 2019.

    Google Scholar 

  223. Wodicka, J. R., A. M. Chambers, G. S. Sangha, C. J. Goergen, and A. Panitch. Development of a glycosaminoglycan derived, selectin targeting anti-adhesive coating to treat endothelial cell dysfunction. Pharmaceuticals (Basel). 10(2):36, 2017.

    Google Scholar 

  224. Woods, E. C., F. Kai, J. M. Barnes, K. Pedram, M. W. Pickup, M. J. Hollander, et al. A bulky glycocalyx fosters metastasis formation by promoting G1 cell cycle progression. Elife. 6:e25752, 2017.

    Google Scholar 

  225. Xia, Y., and B. M. Fu. Investigation of endothelial surface glycocalyx components and ultrastructure by single molecule localization microscopy: stochastic optical reconstruction microscopy (STORM). Yale J. Biol. Med. 91(3):257–266, 2018.

    Google Scholar 

  226. Xu, S., C. H. Ha, W. Wang, X. Xu, M. Yin, F. Q. Jin, et al. PECAM1 regulates flow-mediated Gab1 tyrosine phosphorylation and signaling. Cell Signal. 28(3):117–124, 2016.

    Google Scholar 

  227. Yang, X., J. E. Meegan, M. Jannaway, D. C. Coleman, and S. Y. Yuan. A disintegrin and metalloproteinase 15-mediated glycocalyx shedding contributes to vascular leakage during inflammation. Cardiovasc. Res. 114(13):1752–1763, 2018.

    Google Scholar 

  228. Yang, Y., Y. Zhao, J. Lan, Y. Kang, T. Zhang, Y. Ding, et al. Reduction-sensitive CD44 receptor-targeted hyaluronic acid derivative micelles for doxorubicin delivery. Int. J. Nanomed. 13:4361–4378, 2018.

    Google Scholar 

  229. Yao, Y., A. Rabodzey, and C. F. Dewey, Jr. Glycocalyx modulates the motility and proliferative response of vascular endothelium to fluid shear stress. Am. J. Physiol. Heart Circ. Physiol. 293(2):H1023–H1030, 2007.

    Google Scholar 

  230. Yao, M., L. Wang, M. Fang, W. Zheng, Z. Dong, and D. Yao. Advances in the study of oncofetal antigen glypican-3 expression in HBV-related hepatocellular carcinoma. Biosci. Trends. 10(5):337–343, 2016.

    Google Scholar 

  231. Yen, W., B. Cai, J. Yang, L. Zhang, M. Zeng, J. M. Tarbell, et al. Endothelial surface glycocalyx can regulate flow-induced nitric oxide production in microvessels in vivo. PLoS ONE 10(1):e0117133, 2015.

    Google Scholar 

  232. Yen, W. Y., B. Cai, M. Zeng, J. M. Tarbell, and B. M. Fu. Quantification of the endothelial surface glycocalyx on rat and mouse blood vessels. Microvasc. Res. 83(3):337–346, 2012.

    Google Scholar 

  233. Yeo, T. W., J. B. Weinberg, D. A. Lampah, E. Kenangalem, P. Bush, Y. Chen, et al. Glycocalyx breakdown is associated with severe disease and fatal outcome in Plasmodium falciparum malaria. Clin. Infect. Dis. 69(10):1712–1720, 2019.

    Google Scholar 

  234. Yurdagul, Jr, A., A. C. Finney, M. D. Woolard, and A. W. Orr. The arterial microenvironment: the where and why of atherosclerosis. Biochem. J. 473(10):1281–1295, 2016.

    Google Scholar 

  235. Zeng, Y., R. H. Adamson, F. R. Curry, and J. M. Tarbell. Sphingosine-1-phosphate protects endothelial glycocalyx by inhibiting syndecan-1 shedding. Am. J. Physiol. Heart. Circ. Physiol. 306(3):H363–H372, 2014.

    Google Scholar 

  236. Zeng, Y., E. E. Ebong, B. M. Fu, and J. M. Tarbell. The structural stability of the endothelial glycocalyx after enzymatic removal of glycosaminoglycans. PLoS ONE 7(8):e43168, 2012.

    Google Scholar 

  237. Zeng, Y., and J. Liu. Role of glypican-1 in endothelial NOS activation under various steady shear stress magnitudes. Exp. Cell Res. 348(2):184–189, 2016.

    Google Scholar 

  238. Zeng, Y., X. H. Liu, J. Tarbell, and B. Fu. Sphingosine 1-phosphate induced synthesis of glycocalyx on endothelial cells. Exp. Cell Res. 339(1):90–95, 2015.

    Google Scholar 

  239. Zeng, Y., M. Waters, A. Andrews, P. Honarmandi, E. Ebong, V. Rizzo, et al. Fluid shear stress induces the clustering of heparan sulfate via mobility of glypican-1 in lipid rafts. Am. J. Physiol. Heart Circ. Physiol. 305:811–820, 2013.

    Google Scholar 

  240. Zeng, Y., X. F. Zhang, B. M. Fu, and J. M. Tarbell. The role of endothelial surface glycocalyx in mechanosensing and transduction. Adv. Exp. Med. Biol. 1097:1–27, 2018.

    Google Scholar 

  241. Zhang, X., R. H. Adamson, F. R. Curry, and S. Weinbaum. A 1-D model to explore the effects of tissue loading and tissue concentration gradients in the revised Starling principle. Am. J. Physiol. Heart Circ. Physiol. 291(6):H2950–H2964, 2006.

    Google Scholar 

  242. Zhang, X., R. H. Adamson, F. E. Curry, and S. Weinbaum. Transient regulation of transport by pericytes in venular microvessels via trapped microdomains. Proc. Natl. Acad. Sci. U S A. 105(4):1374–1379, 2008.

    Google Scholar 

  243. Zhang, X., D. Sun, J. W. Song, J. Zullo, M. Lipphardt, L. Coneh-Gould, et al. Endothelial cell dysfunction and glycocalyx: a vicious circle. Matrix Biol. 71–72:421–431, 2018.

    Google Scholar 

  244. Zhang, L., M. Zeng, J. Fan, J. M. Tarbell, F. R. Curry, and B. M. Fu. Sphingosine-1-phosphate maintains normal vascular permeability by preserving endothelial surface glycocalyx in intact microvessels. Microcirculation. 23(4):301–310, 2016.

    Google Scholar 

  245. Zhang, L., M. Zeng, and B. M. Fu. Sphingosine-1-phosphate reduces adhesion of malignant mammary tumor cells MDA-MB-231 to microvessel walls by protecting endothelial surface glycocalyx. Cell Mol. Biol. 63(4):16–22, 2017.

    Google Scholar 

  246. Zhong, Y., K. Goltsche, L. Cheng, F. Xie, F. Meng, C. Deng, et al. Hyaluronic acid-shelled acid-activatable paclitaxel prodrug micelles effectively target and treat CD44-overexpressing human breast tumor xenografts in vivo. Biomaterials 84:250–261, 2016.

    Google Scholar 

  247. Zhou, J., Y. S. Li, and S. Chien. Shear stress-initiated signaling and its regulation of endothelial function. Arterioscler. Thromb. Vasc. Biol. 34(10):2191–2198, 2014.

    Google Scholar 

  248. Zullo, J. A., J. Fan, T. T. Azar, W. Yen, M. Zeng, J. Chen, et al. Exocytosis of endothelial lysosome-related organelles hair-triggers a patchy loss of glycocalyx at the onset of sepsis. Am. J. Pathol. 186(2):248–258, 2016.

    Google Scholar 

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Research supported by National Institutes of Health Grant RO1CA204949.

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Weinbaum, S., Cancel, L.M., Fu, B.M. et al. The Glycocalyx and Its Role in Vascular Physiology and Vascular Related Diseases. Cardiovasc Eng Tech 12, 37–71 (2021). https://doi.org/10.1007/s13239-020-00485-9

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