Scavenger Receptor BI Mediates the Uptake and Transcytosis of HDL in Brain Microvascular Endothelial Cells Independent of PDZK1 and Nitric Oxide

The vascular endothelium supplying the brain exhibits very low paracellular and transcellular permeability which protects the brain from fluctuations in ion concentrations and exposure to circulating toxins. The blood‐brain‐barrier (BBB) consists in large part of a continuous monolayer of endothelial cells joined by intercellular tight junctions that effectively occlude the intercellular space, reducing paracellular permeability. At the same time, the impermeability of the blood‐brain barrier is not absolute, allowing the regulated transport of vari ous molecules such as high‐density lipoprotein (HDL). HDL crosses the blood‐brain barrier by transcytosis but technical limitations have made it difficult to elucidate its regulation. Elucidating the mechanisms of HDL transcytosis across the blood‐brain barrier , in particular, may be significant pathologically as its constituent apolipoprotein ApoAI has been demonstrated to confer a protective effect against Alzheimer disease (AD). Using a combination of spinning‐disc confocal and total internal reflection fluorescence microscopy, we examined the internalization and transcytosis of fluorescently labeled HDL by human primary brain microvascular endothelial cell monolayers. Using these approaches, we report that HDL internalization requires dynamin but not clathrin heavy chain and that its internalization and transcytosis are saturable. Internalized HDL partially co‐localized with the scavenger receptor BI (SR‐BI) and knockdown of SR‐BI significantly attenuated HDL internalization. However, we observed that the adaptor protein PDZK1 ‐ which is critical to HDL‐SR‐BI signaling in other tissues ‐ is not required for HDL uptake in these cells. Furthermore, inhibition of endothelial nitric oxide synthase did not prevent HDL transcytosis but increased HDL internalization while the addition of exogenous nitric oxide had no effect on internalization. Together, these data indicate that HDL transcytosis across the blood‐brain barrier involves a non‐canonical signaling pathway downstream of SR‐BI. Our findings may facilitate manipulation of HDL transcytosis to increase delivery of ApoA1 as a potential therapeutic approach for AD and to increase transport of HDL‐like synthetic particles containing therapeutic drug across the blood‐brain barrier to treat neurodegenerative diseases. Support or Funding Information Karen Fung ‐ Ontario Early Researchers Award from Dr. Gregory Fairn

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