Microvasculature of the Mouse Cerebral Cortex Exhibits Increased Accumulation and Synthesis of Hyaluronan With Aging.

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 neuroinflammation. 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 confirmed 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 profile. 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 significantly 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 neuroinflammation and reduced MV density and function in aging.