Mfsd2a Attenuates Blood-Brain Barrier Disruption After Sub-arachnoid Hemorrhage by Inhibiting Caveolae-Mediated Transcel
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ORIGINAL ARTICLE
Mfsd2a Attenuates Blood-Brain Barrier Disruption After Sub-arachnoid Hemorrhage by Inhibiting Caveolae-Mediated Transcellular Transport in Rats Chongshun Zhao 1 & Junwei Ma 2 & Zhong Wang 1 & Haiying Li 1 & Haitao Shen 1 & Xiang Li 1 & Gang Chen 1 Received: 3 July 2019 / Revised: 9 December 2019 / Accepted: 20 December 2019 # Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract Blood-brain barrier (BBB) disruption is one of the critical mechanisms of brain injury induced by subarachnoid hemorrhage (SAH). Past studies have often focused on the tight junctions of endothelial cells. However, low transcellular transport levels also play an important role in the normal functioning of the BBB. Major facilitator superfamily domain-containing 2a (Mfsd2a) has been demonstrated to be essential for the maintenance of the normal BBB. Our present study aimed to explore the roles and mechanisms of Mfsd2a in BBB disruption after SAH. In this study, a prechiasmatic cistern single-injection model was used to produce experimental SAH in Sprague-Dawley rats. Specific small-interfering RNA and plasmids were used to downregulate and upregulate the expression of Mfsd2a prior to assessments in our SAH model. Omega-3 fatty acid deficiency diet was used to reduce DHA in rat brain. The expression level of Mfsd2a decreased significantly after SAH and reached its lowest level at 72 h post-SAH, which then gradually recovered. At 72 h after SAH, BBB function was disrupted; upregulation of Mfsd2a reversed this damage, whereas downregulation of Mfsd2a exacerbated this damage. These effects were primarily mediated through transcellular transport, especially for changes in caveolae compared to those of tight junctions. After stopping the supply of omega-3 fatty acids, the effect of Mfsd2a on inhibition of caveolae and protection of the blood-brain barrier was eliminated. Taken together, Mfsd2a inhibits caveolae-based transcellular transport by transporting omega-3 fatty acids to protect the BBB after SAH. Keywords Subarachnoid hemorrhage . Blood-brain barrier . Mfsd2a . Caveolae . Omega-3 fatty acids
Introduction Subarachnoid hemorrhage (SAH), which is mostly caused by a ruptured aneurysm, is a devastating cerebrovascular disease with several mechanisms that threaten the normal functioning of the central nervous system (CNS) [1–3]. Epidemiological Chongshun Zhao, Junwei Ma and Zhong Wang contributed equally to this work. * Xiang Li [email protected] * Gang Chen [email protected] 1
Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, 188 Shizi Street,, Suzhou 215006, Jiangsu Province, China
2
Department of Neurosurgery, The Affiliated Hospital of Qingdao University, 16 Jiangsu Road, Qingdao 266003, Shandong Province, China
investigation reported that the incidence of aneurysmal SAH ranges from 2 per 100,000 individuals each year in ChinaBeijing, to as much as 22.5 per 100,000 individuals each year in Finland [4]. The mortalit
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