Targeting Hyaluronan in Vascular Diseases with Special Reference to Diabetic Macroangiopathy
Journal Title: Biomedical Journal of Scientific & Technical Research (BJSTR) - Year 2019, Vol 12, Issue 3
Abstract
Vascular Extracellular Matrix (ECM) is a dynamic structure, which regulates blood vessel morphogenesis, provides organizational stability, and modulates various aspects of cell behavior [1]. Hyaluronan (HA) represents one of the most abundant macromolecules of the vascular wall. One of its main functions is to maintain blood vessel integrity [2]. Thus, any alteration in the metabolism of HA can predispose to the development and progression of atherosclerotic vascular diseases including diabetic macroangiopathy [3,4]. HA is a multifunctional linear glycosaminoglycan, composed of repeating disaccharide units of D-Glucuronic Acid (GlcUA) and N-Acetylglucosamine (GlcNac) (Figure 1). It is synthesized by specific plasma membrane glycosyltransferases, namely Hyaluronan Synthases 1-3 (HAS 1-3) [5]. The HASes exhibit distinctive enzymatic properties and use the cytosolic pool of UDP-sugars as substrates. The functions of HA are versatile and partly depend on its molecular size. For example, High Molecular Weight (HMW) HA possesses anti-inflammatory and immunosuppressive properties, whereas Low Molecular Weight (LMW) HA is a potent pro-inflammatory molecule [6]. The action of HA is also greatly influenced by its interactions with other ECM macromolecules such as lecticans, and cell membrane receptors, e.g. Cluster Determinant 44 (CD44) [7,8]. The turnover of HA is tissue specific and its half-life varies from 12 to 72 hours [9]. While HASes are responsible for the synthesis of HA, Hyaluronidases (HYALs) are enzymes responsible for its degradation.HA is expressed in every type of blood vessel, and for example in arteries it can be detected in all three layers, mostly in the intima and adventitia and also in small amounts in the media. By maintaining intact endothelial glycocalyx, HA displays a pivotal role in vascular biology [10,11]. Overexpression of HA is characteristic for diabetic macroangiopathy [12]. Accumulation of HA occurs in response to hyperglycemia (Figure 2). This results in enhanced Vascular Smooth Muscle Cell (VSMC) proliferation and migration, and altered inflammatory cell adhesion properties [3,13]. Also increased HYAL activity and generation of Reactive Oxygen Species (ROS) are typical in diabetes. These both lead to HA fragmentation, which damages endothelial glycocalyx and thereby compromises vascular integrity even further [2,14]. Overall, dysregulation of HA turnover initiates processes that lead to various vascular complications including micro- and macroangiopathy in diabetic patients [15]. Thus, approaches targeting HA offer promising strategies (Figure 3) for novel therapeutic interventions in atherosclerotic vascular diseases.
Authors and Affiliations
Annele Sainio, Hannu Järveläinen
Keywords
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- EP ID EP586012
- DOI 10.26717/BJSTR.2019.12.002269
- Views 177
- Downloads 0
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