title: Changes in hyaluronan production and metabolism following ischaemic stroke in man.
abstract: The extent of recovery from stroke is dependent on the survival of neurons, particularly in peri-infarcted regions. Angiogenesis is critical for the development of new microvessels and leads to re-formation of collateral circulation, reperfusion and better recovery. Hyaluronan (HA) is an important component of the brain extracellular matrix and a regulator of cellular differentiation, migration, proliferation and angiogenesis. We have found that the production of total HA and low molecular mass 3-10 disaccharides of HA (o-HA) was increased in post-mortem tissue and in the serum of patients 1, 3, 7 and 14 days (peaking at 7 days) after ischaemic stroke. Hyaluronidase activity was also increased in serum samples (peaking after 3 days), which might explain the subsequent increase in o-HA. Affinity-histochemical staining was performed using a HA-specific biotinylated binding protein, and it showed enhanced deposition of HA in blood vessels and intracellularly as well as in the nuclei of peri-infarcted neurons. Western blotting and immunohistochemistry demonstrated upregulation of HA synthases (HAS1 and 2) and hyaluronidases (HYAL1 and 2) in inflammatory cells from both stroke and peri-infarcted regions of the brain. HYAL1 was upregulated in microvesssels and intracellularly in neurons, whilst HAS2 became translocated into the nuclei of neurons in peri-infarcted areas. Receptor for HA-mediated motility was observed intracellularly and in the nuclei of neurons, in the tunica media of larger blood vessels and in the endothelial cells of microvessels in stroke-affected tissue, whilst expression of other receptors for HA, CD44 and tumour necrosis factor-stimulated gene 6 (TSG-6) were mainly increased in infiltrating mononuclear cells from inflammatory regions. The data presented here demonstrate that HA breakdown is a feature of the acute stage of stroke injury. Increased o-HA production soon after stroke may be detrimental through enhancement of the inflammatory response, whilst activation of HA and/or o-HA-induced cellular signalling pathways in neurons and microvessels may impact on the remodelling process by stimulating angiogenesis and revascularization, as well as the survival of susceptible neurons.
authors.affiliation: Department of Biology, Chemistry and Health Science, Manchester Metropolitan University, Liverpool, UK.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Al'Qteishat
authors.forename: John
authors.initials: J
authors.lastname: Gaffney
authors.forename: Jerzy
authors.initials: J
authors.lastname: Krupinski
authors.forename: Francisco
authors.initials: F
authors.lastname: Rubio
authors.forename: David
authors.initials: D
authors.lastname: West
authors.forename: Shant
authors.initials: S
authors.lastname: Kumar
authors.forename: Patricia
authors.initials: P
authors.lastname: Kumar
authors.forename: Nicholas
authors.initials: N
authors.lastname: Mitsios
authors.forename: Mark
authors.initials: M
authors.lastname: Slevin
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D001808:Blood Vessels / Q000378:metabolism; D001921:Brain / Q000098:blood supply / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000378:metabolism; D002544:Cerebral Infarction / Q000378:metabolism*; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D005260:Female; D014453:Glucuronosyltransferase / Q000378:metabolism; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism; D000076002:Hyaluronan Synthases; D006820:Hyaluronic Acid / Q000097:blood / Q000378:metabolism*; D006821:Hyaluronoglucosaminidase / Q000097:blood; D008297:Male; D008875:Middle Aged; D009474:Neurons / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D015815:Cell Adhesion Molecules; D016326:Extracellular Matrix Proteins; D018960:Hyaluronan Receptors; C072273:TNFAIP6 protein, human; C098946:hyaluronan-mediated motility receptor; D006820:Hyaluronic Acid; D014453:Glucuronosyltransferase; D000076002:Hyaluronan Synthases; D006821:Hyaluronoglucosaminidase