Hyaluronan regulation of vascular integrity

Abstract

Vascular integrity or the maintenance of blood vessel continuity is a fundamental process regulated, in part, by the endothelial glycocalyx and cell-cell junctions. Defects in endothelial barrier function are an initiating factor in several disease processes including atherosclerosis, ischemia/reperfusion, tumor angiogenesis, cancer metastasis, diabetes, sepsis and acute lung injury. The glycosaminoglycan, hyaluronan (HA), maintains vascular integrity through endothelial glycocalyx modulation, caveolin-enriched microdomain regulation and interaction with endothelial HA binding proteins. Certain disease states increase hyaluronidase activity and reactive oxygen species (ROS) generation which break down high molecular weight HA to low molecular weight fragments causing damage to the endothelial glycocalyx. Further, these HA fragments can activate specific HA binding proteins upregulated in vascular disease to promote actin cytoskeletal reorganization and inhibition of endothelial cell-cell contacts. This review focuses on the crucial role of HA in vascular integrity and how HA degradation promotes vascular barrier disruption.

Keywords: CD44; Endothelial permeability; HABP2; TLR2; TLR4; actin cytoskeleton; caveolin-1; caveolin-enriched microdomain; glycocalyx; versican.

Figure 1

The Chemical Structure of hyaluronan (HA). HA is composed of linear repeating disaccharide units consisting of D-glucuronic acid and N-acetylglucosamine [19].

Figure 2

Hyaiuronan Regulation of Endotheiiai Barrier Function and the Actin Cytoskeieton. HMW-HA (∼1 million Da) induces a dose-dependent increase in human pulmonary microvascuiar EC barrier function (A) and promotes cortical actin ring formation (B). The arrows indicate areas of cortical actin associated with EC contacts. In contrast, LMW-HA (∼2,500 Da) promotes a biphasic response resulting in EC barrier disruption (C) and actin stress fiber formation (D). The arrows indicate gap formations between ECs. This research was originally published in The Journal of Biological Chemistry (Singleton et al., J. Biol. Chem., 2006, 10;281(45):34381-93) © the American Society for Biochemistry and Molecular Biology [18].

Figure 3

Hyaluronan Regulation of Normal and Impaired Vascular Integrity. High molecular weight hyaluronan (HMW-HA), the major non-sulfated glycosaminoglycan in the body, maintains vascular integrity through endothelial glycoca-lyx modulation, caveolin-enriched microdomain (CEM) regulation and interaction with endothelial HA binding proteins (upper panel). In the glycocalyx, HMW-HA interacts with proteoglycans (including versican) and glycoproteins to form a negatively charged “mesh” located on the luminal side of the endothelium in all blood vessels [8]. This glycocalyx regulates vascular permeability and incorporates serum proteins such as albumin, fibrinogen and extracellular super-oxide dismutase [15]. HMW-HA binds to and inhibits the EC barrier disrupting activity of the extracellular serine protease HABP2 [130]. In addition, HMW-HA binds to the transmembrane receptor, CD44s (standard form), in CEM which results in Akt-mediated Tiaml activation and Racl-GTP formation Ieadingto cortical actin formation and strengthening of EC-EC contacts [18]. Further, HMW-HA recruits several other actin regulatory proteins to CEM including annexin A2, protein S100-A10, filamin-A and filamin-B which enhance cortical actin formation and vascular integrity [4]. In disease states such as atherosclerosis, ischemia/reperfusion, tumor angiogenesis, cancer metastasis, diabetes, sepsis and acute lung injury, there is impaired vascular integrity (lower panel). Damage to the endothelium generates reactive oxygen species (ROS) and hyaiuronidase activation lead to generation of low molecular weight HA fragments (LMW-HA) [17, 28, 100]. In addition to CD44vlO (variant 10) ligation, LMW-HA binds to and activates HABP2 which induces protease-activated receptor (PAR) activation in EC [. 130]. These events promote RhoA-GTP formation and stimulation of rho kinase (ROCK) activity Ieadingto actin stress fiber formation and EC barrier disruption [18, 130]. Disruption of the endothelium promotes leakage of fluid and protein into the underlying tissue [1, 2, 6, 106, 134].