Brain Advance Access originally published online on May 26, 2006
Brain 2006 129(8):2158-2176; doi:10.1093/brain/awl139
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Changes in hyaluronan production and metabolism following ischaemic stroke in man
1 Department of Biology, Chemistry and Health Science, Manchester Metropolitan University Liverpool, UK 2 University of Manchester and Christie Hospital Manchester, Liverpool, UK 3 Department of Biochemistry, University of Liverpool Liverpool, UK 4 Department of Neurology, Stroke Unit, Hospital Universitario de Bellvitge (HUB) Barcelona, Spain 5 Insitut D'Investigació Biomedica de Belvitge (IDIBELL) Barcelona, Spain
Correspondence to: Mark Slevin, Department of Biology, Chemistry and Health Science, Manchester Metropolitan University, Manchester M1 5GD, UK E-mail: m.a.slevin{at}mmu.ac.uk
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.
Key Words: RHAMM; hyaluronan; hyaluronidase; hyaluronan synthase; ischaemic stroke
Abbreviations: BSA, bovine serum albumin; EC, endothelial cells; ECM, extracellular matrix; HA, hyaluronan; o-HA, oligosaccharides of hyaluronan; HABP, hyaluronan binding protein; HAS, hyaluronan synthase; HYAL, hyaluronidase; IS, ischaemic stroke; PBS, phosphate-buffered saline; RHAMM, receptor for hyaluronan-mediated motility; RT–PCR, reverse transcription–polymerase chain reaction; SDS–PAGE, sodium dodecyl sulphate–polyacrylamide gel electrophoresis; SSS, Scandinavian Stroke Scale; TSG-6, tumour necrosis factor-stimulated gene 6
Received January 20, 2006. Revised April 24, 2006. Accepted April 26, 2006.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  S.-C. Tang, T. V. Arumugam, X. Xu, A. Cheng, M. R. Mughal, D. G. Jo, J. D. Lathia, D. A. Siler, S. Chigurupati, X. Ouyang, et al. Pivotal role for neuronal Toll-like receptors in ischemic brain injury and functional deficits PNAS, August 21, 2007; 104(34): 13798 - 13803. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Schulz, U. Schumacher, and P. Prehm Hyaluronan Export by the ABC Transporter MRP5 and Its Modulation by Intracellular cGMP J. Biol. Chem., July 20, 2007; 282(29): 20999 - 21004. [Abstract] [Full Text] [PDF]
|
|