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Fig. 3 | Fluids and Barriers of the CNS

Fig. 3

From: The blood–brain barrier and the neurovascular unit in subarachnoid hemorrhage: molecular events and potential treatments

Fig. 3Fig. 3

Reaction of endothelial cells to subarachnoid hemorrhage. a ECs disruption after SAH. BBB dysfunction facilitates the passage of blood components (Hb, Tb and, serum proteins) into the perivascular space. In response to TLR4 activation, p53 and NF-κB are activated, levels of MAP4K4 and ROS are increased, and CHOP is upregulated, resulting in the downregulation of ZO, claudins, JAM, and VE-cadherin, that together increase BBB permeability. ER stress caused by Bax and PUMA upregulation activates caspase-3 and causes DNA fragmentation and cell apoptosis. Caspase-3 activation also accrues via caspase-8 signaling triggered by the TNF-α receptor. CHOP upregulation decreases Bcl-2 expression and upregulates Bim. MMP-9 upregulation reduces collagen IV and laminin proteins in the basal lamina, thus increasing BBB permeability. The upregulation of adhesion molecules promotes leukocyte infiltration, which decreases NO via myeloperoxidase. Cyt c upregulation causes cell death; VSMC contraction is regulated by PGF2α upregulation in response to upregulation of TXA2 and TLR4 activation. ECs are stimulated by MAC, upregulating PDGF-BB production and affecting VSMC. VEGF upregulation leads to collagen IV exposure and thus to platelet adhesion. b ECs protection mechanisms. Bcl-2 upregulation caused by S1P1/PI3K/Akt and JAK2/STAT3 pathways is due to TM activation and anti-inflammatory cytokine production, respectively. Bcl-2 and STAT-3 upregulation suppress cell apoptosis. Upregulation of OPN activates Akt, decreasing GSK3β expression and TJ protein upregulation. AMPKα upregulation and Akt activation can also increase phosphorylated eNOS, resulting in increased NO and VSMC dilatation. Downregulation of NF-κB, caspase-3, and BAX results from Akt activation. NF-κB is also downregulated by ApoE upregulation and decreased expression of CypA. TJs are upregulated by activation of the ErbB4 receptor, increased Yap, and PIK3CB

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