Ischemic factor-induced increases in cerebral microvascular endothelial cell Na/H exchange activity and abundance: evidence for involvement of ERK1/2 MAP kinase

Abstract

Brain edema forms rapidly in the early hours of ischemic stroke by increased secretion of Na, Cl, and water into the brain across an intact blood-brain barrier (BBB), together with swelling of astrocytes as they take up the ions and water crossing the BBB. Our previous studies provide evidence that luminal BBB Na-K-Cl cotransport (NKCC) and Na/H exchange (NHE) participate in ischemia-induced edema formation. NKCC1 and two NHE isoforms, NHE1 and NHE2, reside predominantly at the luminal BBB membrane. NKCC and NHE activities of cerebral microvascular endothelial cells (CMEC) are rapidly stimulated by the ischemic factors hypoxia, aglycemia, and AVP, and inhibition of NKCC and NHE activities by bumetanide and HOE642, respectively, reduces brain Na uptake and edema in the rat middle cerebral artery occlusion model of stroke. The present study was conducted to further explore BBB NHE responses to ischemia. We examined whether ischemic factor-stimulated NHE activity is sustained over several hours, when the majority of edema forms during stroke. We also examined whether ischemic factors alter NHE1 and/or NHE2 protein abundance. Finally, we conducted initial studies of ERK1/2 MAP kinase involvement in BBB NHE and NKCC responses to ischemic factors. We found that hypoxia, aglycemia, and AVP increase CMEC NHE activity through 5 h and that NHE1, but not NHE2, abundance is increased by 1- to 5-h exposures to these factors. Furthermore, we found that these factors rapidly increase BBB ERK1/2 activity and that ERK1/2 inhibition reduces or abolishes ischemic factor stimulation of NKCC and NHE activities.

Endothelial Na+/H+ exchanger NHE1 participates in redox-sensitive leukocyte recruitment triggered by methylglyoxal

“…Previous studies have shown a crucial role of NHE-dependent functions in the brain microvascular endothelium [ 36 - 38 ]. These studies, however, preclude us to draw mechanistic parallels of NHE-dependent functions in brain microvascular endothelial cells to peripheral endothelial cells due to their distinct features.…”

“…The plasma membrane transport protein NHE1 regulates cellular pH and volume and, thus, participates in a multitude of physiological functions such as proliferation, migration and apoptosis [ 32 ]. Endothelial cells express the Na + /H + exchanger isoforms NHE1 and NHE2 that regulate functions such as endocytosis [ 33 ], apoptosis [ 34 ] and blood brain barrier [ 35 - 38 ]. NHE1 is constitutively phosphorylated and additional phosphorylation enhances its activity [ 39 ].…”

Model Roles of the Hypothalamo-Neurohypophysial System in Neuroscience Study

“…VP release and expression of its receptors in the brain increase significantly following ischemia, trauma or subarachnoid hemorrhage in patients and in animal models of these diseases [134]. VP can increase ion transport across the cell membrane and the blood-brain barrier [135] while increasing AQP4 expression in astrocytes and thus promoting cytotoxic edema [136]. In parallel with the direct effect on hydromineral balance, excessive VP also causes brain arteriole constriction and worsens tissue hypoxia [137], thereby worsening brain edema through oxygen and glucose deprivation.…”

Bumetanide-induced NKCC1 inhibition attenuates oxygen–glucose deprivation-induced decrease in proliferative activity and cell cycle progression arrest in cultured OPCs via p-38 MAPKs

“…NKCC1 plays important roles in maintaining CNS functions, including regulatiing neuronal Na þ influx during acute excitotoxicity, amyloid precursor protein deposition, cell migration, and astrocyte swelling (Chen et al, 2005;Garzon-Muvdi et al, 2012;Kahle et al, 2009). NKCC1-dependent MAPK signaling networks can modulate the protein expression of cyclins and cyclin-dependent protein kinases (cdks), which play pivotal roles in controlling the cell cycle (Capo-Aponte et al, 2007;Yuen et al, 2014). Therefore, activation of NKCC1 is proposed to be an essential step during cell proliferation.…”