Brain Advance Access published online on May 26, 2006
Brain, doi:10.1093/brain/awl139
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1 Department of Biology, Chemistry and Health Science, Manchester Metropolitan University, Manchester, UK
* To whom correspondence should be addressed. 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.
Received January 20, 2006
Revised April 24, 2006
Accepted April 26, 2006
Article
Changes in hyaluronan production and metabolism following ischaemic stroke in man
Ahmed Al'Qteishat 1,
John Gaffney 1,
Jerzy Krupinski 2,
Francisco Rubio 2,
David West 3,
Shant Kumar 4,
Patricia Kumar 1,
Nicholas Mitsios 1,
and
Mark Slevin 1 *
2 Department of Neurology, Stroke Unit, Hospital Universitario de Bellvitge (HUB), Barcelona, Spain; Insitut D'Investigació Biomedica de Belvitge (IDIBELL), Barcelona, Spain
3 Department of Biochemistry, University of Liverpool, Liverpool, UK
4 University of Manchester and Christie Hospital, Manchester, UK
Mark Slevin, E-mail: m.a.slevin{at}mmu.ac.uk
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