Regulation of brain vascular endothelial cell ferroptosis by hyaluronan

Oregon Health & Science University, Portland OR

Investigators

Abstract

PROJECT SUMMARY This project is focused on understanding the mechanisms underlying brain vascular endothelial cell (BVEC) disruption following vascular brain injury (VBI). Vascular contributions to cognitive impairment and dementia (VCID) are the second leading cause of dementia, caused in part by VBI and blood-brain barrier dysfunction. VBI can cause the degeneration of BVECs, leading to brain capillary leakages that promote neuroinflammation and neurodegenerative disease. Accumulating evidence supports a role for ferroptosis, a form of programmed cell death involving iron overload and reactive oxygen species (ROS)-dependent lipid peroxide accumulation, in the degeneration of BVECs. A recent study suggested that ferroptosis can be inhibited following traumatic brain injury by the glycosaminoglycan hyaluronan (HA). We find that BVECs express elevated levels of the Cell Migration and Hyaluronan Binding Protein (CEMIP), a hyaluronidase, in patients with VBI. Elevated CEMIP expression is accompanied by increased HA synthesis and expression of the CD44 transmembrane HA receptor. Based on these findings, our overarching hypothesis is that HA protects BVECs from ferroptosis through a CD44-depedent mechanism. However, if CEMIP remains elevated, HA is digested, leading to the initiation of BVEC ferroptosis and BBB breakdown. We will test this hypothesis in the following specific aims: (1) To test the hypothesis that HMW HA inhibits BVEC cell ferroptosis through a CD44-dependent mechanism; (2) To test the hypothesis that HA digestion by CEMIP increases BVEC ferroptosis; and (3) To test the hypothesis that CEMIP inhibitors can prevent BVEC ferroptosis. These studies will provide mechanistic insights into the pathogenesis of VCID and will determine the feasibility of targeting HA signaling and CEMIP to protect BVECs, and possibly prevent blood-brain barrier dysfunction, following VBI.