© The Author 2016. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com. Journals of Gerontology: Biological Sciences cite as: J Gerontol A Biol Sci Med Sci, 2017, Vol. 72, No. 6, 740–746 doi:10.1093/gerona/glw213 Advance Access publication November 15, 2016 Original Article Microvasculature of the Mouse Cerebral Cortex Exhibits Increased Accumulation and Synthesis of Hyaluronan With Aging May J. Reed, 1 Robert B. Vernon, 2 Mamatha Damodarasamy, 1 Christina K. Chan, 2 Thomas N. Wight, 2 Itay Bentov, 3 and William A. Banks 1,4 1 Department of Medicine, University of Washington, Seattle. 2 Matrix Biology Program, Benaroya Research Institute at Virginia Mason, Seattle, Washington. 3 Department of Anesthesia and Pain Medicine, University of Washington, Seattle. 4 VA Puget Sound Health Care System, Geriatric Research Education and Clinical Center, Seattle, Washington. Address correspondence to May J. Reed, MD, Department of Medicine, University of Washington, Harborview Medical Center, 325 9th Avenue, Box 359625, Seattle, WA 98104. E-mail: mjr@uw.edu Received May 18, 2016; Accepted October 10, 2016 Decision Editor: Rafael de Cabo, PhD Abstract The microvasculature of the aged brain is less dense and more vulnerable to dysfunction than that of the young brain. Brain microvasculature is supported by its surrounding extracellular matrix, which is comprised largely of hyaluronan (HA). HA is continually degraded into lower molecular weight forms that induce neuroinfammation. We examined HA associated with microvessels (MV) of the cerebral cortex of young (4 months), middle-aged (14 months), and aged (24–26 months) mice. We confrmed that the density of cortical MV decreased with age. Perivascular HA levels increased with age, but there was no age-associated change in HA molecular weight profle. MV isolated from aged cortex had more HA than MV from young cortex. Examination of mechanisms that might account for elevated HA levels with aging showed increased HA synthase 2 (HAS2) mRNA and protein in aged MV relative to young MV. In contrast, mRNAs for HA-degrading hyaluronidases or hyaladherins that mitigate HA degradation showed no changes with age. Corresponding to increased HAS2, aged MV synthesized signifcantly more HA (of all molecular weight classes) in vitro than young MV. We propose that increased HA synthesis and accumulation in brain MV contributes to neuroinfammation and reduced MV density and function in aging. Keywords: Aging—Brain—Microvasculature—Hyaluronan—Microvessels It is increasingly appreciated that the microvasculature of the aged brain is less dense and more vulnerable to injury than that of the young brain (1–3). Changes in the brain microvasculature with aging result in less effective perfusion and increased risk of exposure of brain tissue to deleterious substances from the systemic circulation (4–6). The resiliency of the microvasculature is determined, in part, by the extracellular matrix (ECM) that surrounds it (7). This ECM is comprised largely of hyaluronan (HA), an anionic, nonsulfated glycosaminoglycan comprised of the repeating disaccharide unit d-glucuronic acid and N-acetyl-D-glucosamine. In the brain, HA is synthesized by multiple cell types, including cells of the microvessels (MV), which consist of vascular endothelial cells and their associated pericytes and astrocytes. Associated with the HA are hyaladherins: a broad group of HA-binding molecules that include chondroitin sulfate-rich proteoglycans (e.g., aggrecan, versican, neurocan, and brevican), the glycoprotein tenascin-R, and tumor necrosis factor- stimulated gene 6 protein (TSG-6) (8–11). HA linkage to these and other components of brain ECM is mediated by proteins, such as Bral1, which confer additional stability (12). HA is produced by membrane-bound HA synthases (HASes) which exist in at least three isoforms (HAS1, 2, and 3) that produce HA of different chain lengths. HA is usually synthesized in forms with high molecular weights (HMW) (e.g., >1,000 kDa) that are subsequently cleaved by hyaluronidases (HYALs) into shorter chain lengths with a wide range of MW. There are at least six HYAL iso- forms with consensus that HYALs 1–3 could be detected in the set- ting of brain injury (13). The biological activity of HA is determined by its size, with many studies showing that HA of relatively low MW Downloaded from https://academic.oup.com/biomedgerontology/article-abstract/72/6/740/2525929 by guest on 24 May 2020