Hyaluronan biology: A complex balancing act of structure, function, location and context.

The newly emergent novel coronavirus disease 2019 (COVID-19) outbreak, which is caused by SARS-CoV-2 virus, has posed a serious threat to global public health and caused worldwide social and economic breakdown. Angiotensin-converting enzyme 2 (ACE2) is expressed in human vascular endothelium, respiratory epithelium, and other cell types, and is thought to be a primary mechanism of SARS-CoV-2 entry and infection. In physiological condition, ACE2 via its carboxypeptidase activity generates angiotensin fragments (Ang 1–9 and Ang 1–7), and plays an essential role in the renin-angiotensin system (RAS), which is a critical regulator of cardiovascular homeostasis. SARS-CoV-2 via its surface spike glycoprotein interacts with ACE2 and invades the host cells. Once inside the host cells, SARS-CoV-2 induces acute respiratory distress syndrome (ARDS), stimulates immune response (i.e., cytokine storm) and vascular damage. SARS-CoV-2 induced endothelial cell injury could exacerbate endothelial dysfunction, which is a hallmark of aging, hypertension, and obesity, leading to further complications. The pathophysiology of endothelial dysfunction and injury offers insights into COVID-19 associated mortality. Here we reviewed the molecular basis of SARS-CoV-2 infection, the roles of ACE2, RAS signaling, and a possible link between the pre-existing endothelial dysfunction and SARS-CoV-2 induced endothelial injury in COVID-19 associated mortality. We also surveyed the roles of cell adhesion molecules (CAMs), including CD209L/L-SIGN and CD209/DC-SIGN in SARS-CoV-2 infection and other related viruses. Understanding the molecular mechanisms of infection, the vascular damage caused by SARS-CoV-2 and pathways involved in the regulation of endothelial dysfunction could lead to new therapeutic strategies against COVID-19.

https://www.mdpi.com/2073-4409/9/7/1652/pdf

COVID-19, Renin-Angiotensin System and Endothelial Dysfunction

Hyaluronan (HA) is a ubiquitous glycosaminoglycan of the extracellular matrix. It is present in the endothelial glycocalyx covering the apical surface of endothelial cells. The endothelial glycocalyx regulates blood vessel permeability and homeostasis. HA plays a central role in numerous functions of the endothelial surface layer, protecting the endothelial cells, regulating the barrier permeability, and ensuring mechanosensing, which is essential to nitric oxide production and flow-induced vasodilation. During acute injury, inflammatory conditions, or many other pathologic conditions, the endothelial glycocalyx is damaged, and its degradation is accompanied by shedding of one or more glycocalyx components into the blood. Syndecan-1, heparan sulfate, and HA are the main components whose shedding has been claimed to represent the endothelial glycocalyx state of health. This review focuses on endothelial glycocalyx HA and highlights its key roles in the functions of the endothelial glycocalyx, its shedding in several pathologic conditions such as sepsis, diabetes, chronic and acute kidney injury, ischemia/reperfusion, atherosclerosis, and inflammation, which are all accompanied by increased circulating HA levels. Plasma/serum HA level is becoming recognized as a biomarker of endothelial glycocalyx damage in select pathologies. Hyaluronidase, the main HA-degrading enzyme, and its involvement in the impairment of endothelial glycocalyx are also addressed.

Endothelial Glycocalyx Impairment in Disease: Focus on Hyaluronan Shedding

Revisiting pharmacology of oxidative stress and endothelial dysfunction in cardiovascular disease: Evidence for redox-based therapies.

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

/pdf/the-glycocalyx-and-its-role-in-vascular-physiology-and-44kdds5m69.pdf

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

Endothelial cell dysfunction and glycocalyx - A vicious circle.

Along with the recognition of a crucial role played by endothelial dysfunction secondarily igniting cardiovascular, pulmonary, and renal complications, investigational focus has extended toward endothelial glycocalyx. This delicate coating of cells, including the vascular endothelium, regulates permeability, leukocyte traffic, nitric oxide production, and coagulation, and harbors diverse growth and survival factors. In this brief overview, we discuss the metabolic signatures of sepsis as they relate to the loss of glycocalyx integrity and highlight the contribution of several proteases, heparanase, and hyaluronidase to the shedding of glycocalyx. Clinical manifestations of glycocalyx degradation in unraveling acute respiratory distress syndrome and the cardiovascular, microcirculatory, and renal complications of sepsis are concisely presented. Finally, we list therapeutic strategies for preventing the degradation of, and for restoration of, the glycocalyx.

Glycocalyx in Endotoxemia and Sepsis

The present disclosure relates to compositions and methods for restoring endothelial glycocalyx. Exemplary compositions include nanoparticle compositions of preassembled glycocalyx.

Compositions and methods for restoring endothelial glycocalyx

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Endothelial cell dysfunction and glycocalyx - A vicious circle.

Glycocalyx in Endotoxemia and Sepsis

Compositions and methods for restoring endothelial glycocalyx