Apelin-13 Protects against Ischemic Blood-Brain Barrier Damage through the Effects of Aquaporin-4

Abstract

Background: Apelin-13 has been found to have protective effects on many neurological diseases, including cerebral ischemia. However, whether Apelin-13 acts on blood-brain barrier (BBB) disruption following cerebral ischemia is largely unknown. Aquaporin-4 (AQP4) has a close link with BBB due to the high concentration in astrocyte foot processes and regulation of astrocytes function. Here, we aimed to test Apelin-13′s effects on ischemic BBB injury and examine whether the effects were dependent on AQP4. Methods: We detected the expression of AQP4 induced by Apelin-13 injection at 1, 3, and 7 days after middle cerebral artery occlusion. Meanwhile, we examined the effects of Apelin-13 on neurological function, infarct volume, and BBB disruption owing to cerebral ischemia in wild type mice, and tested whether such effects were AQP4 dependent by using AQP4 knock-out mice. Furthermore, we assessed the possible signal transduction pathways activated by Apelin-13 to regulate AQP4 expression via astrocyte cultures. Results: It was found that Apelin-13 highly increased AQP4 expression as well as reduced neurological scores and infarct volume. Importantly, Apelin-13 played a role of BBB protection in both types of mice by reducing BBB permeability, increased vascular endothelial growth factor, upregulated endothelial nitric oxide synthase, and downregulated inducible NOS. In morphology, we demonstrated Apelin-13 suppressed tight junction opening and endothelial cell swelling via electron microscopy detection. Meanwhile, Apelin-13 also alleviated apoptosis of astrocytes and promoted angiogenesis. Interestingly, effects of AQP4 on neurological function and infarct volume varied with time course, while AQP4 elicited protective effects on BBB at all time points. Statistical analysis of 2-way analysis of variance with replication indicated that AQP4 was required for these effects. In addition, Apelin-13 upregulated phosphorylation of extracellular signal-regulated kinase (ERK) and Akt as well as AQP4 protein in cultured astrocytes. The latter was inhibited by ERK and phosphatidylinositol 3′-kinase (PI3K) inhibitors. Conclusion: Our data suggest that Apelin-13 protects BBB from disruption after cerebral ischemia both morphologically and functionally, which is highly associated with the increased levels of AQP4, possibly through the activation of ERK and PI3K/Akt pathways. This study provides double targets to protection of ischemic BBB damage, which can present new insights to drugs development.

The Apelin/APJ System in Psychosis and Neuropathy

“…Apelin-13 (i.c.v., 50, 100 µg/kg) ameliorated I/R injury in the mouse brain by activating the PI3K/Akt and ERK1/2 signaling pathways (Yang et al, 2014). Apelin-13 (i.c.v., 50 µg/kg) alleviated damage to the mouse blood-brain barrier from ischemic injury via improvement of aquaporin-4 (AQP4), and the increase of AQP4 caused by apelin-13 was mediated through the PI3K/Akt and ERK pathways (Chu et al, 2016). I.c.v.…”

Increased apelin receptor gene expression in the subfornical organ of spontaneously hypertensive rats

“…In the brain aplnr is present at low levels in normal human meningeal blood vessels [72], and both apln and ir-apelin, and aplnr expression have been found in microvascular proliferations in human glioblastoma specimens [72,73]. Aplnr is expressed in the ECs of some vessels in the rodent brain [74], and apelin promotes angiogenesis and endothelial function after brain insults in mice [75,76], and stimulates the proliferation of mouse brain microvasculature-derived ECs [77]. The potential expression of components of the apelinergic system in brain ECs, e.g.…”

The Protective Effects and Mechanisms of Apelin/APJ System on Ischemic Stroke: A Promising Therapeutic Target

“…Similarly, apelin deficiency causes compromised angiogenesis and functional recovery and increased susceptibility to ischemic injury (93). Apelin-13 protects the blood-brain barrier (BBB) from ischemic injury by upregulating aquaporin-4 (AQP4) and VEGF via the ERK and PI3K/AKT pathways (46). In conclusion, the apelin/APJ system not only protects neurons from ischemic injury but also facilitates angiogenesis and prognosis of stroke, which may be mediated by the VEGF-VEGFR2 signaling pathway.…”