title: Regulation of Dipeptidyl Peptidase IV in the Post-stroke Rat Brain and In Vitro Ischemia: Implications for Chemokine-Mediated Neural Progenitor Cell Migration and Angiogenesis.
abstract: Cerebral ischemia evokes abnormal release of proteases in the brain microenvironment that spatiotemporally impact angio-neurogenesis. Dipeptidyl peptidase IV (DPPIV), a cell surface and secreted protease, has been implicated in extracellular matrix remodeling by regulating cell adhesion, migration, and angiogenesis through modifying the functions of the major chemokine stromal-derived factor, SDF1. To elucidate the possible association of DPPIV in ischemic brain, we examined the expression of DPPIV in the post-stroke rat brain and under in vitro ischemia by oxygen glucose deprivation (OGD). We further investigated the effects of DPPIV on SDF1 mediated in vitro chemotactic and angiogenic functions. DPPIV protein and mRNA levels were significantly upregulated during repair phase in the ischemic cortex of the rat brain, specifically in neurons, astrocytes, and endothelial cells. In vitro exposure of Neuro-2a neuronal cells and rat brain endothelial cells to OGD resulted in upregulation of DPPIV. In vitro functional analysis showed that DPPIV decreases the SDF1-mediated angiogenic potential of rat brain endothelial cells and inhibits the migration of Neuro-2a and neural progenitor cells. Western blot analyses revealed decreased levels of phosphorylated ERK1/2 and AKT in the presence of DPPIV. DPPIV inhibitor restored the effects of SDF1. Proteome profile array screening further revealed that DPPIV decreases matrix metalloproteinase-9, a key downstream effector of ERK-AKT signaling pathways. Overall, delayed induction of DPPIV in response to ischemia/reperfusion suggests that DPPIV may play an important role in endogenous brain tissue remodeling and repair processes. This may be mediated through modulation of SDF1-mediated cell migration and angiogenesis.
authors.affiliation: Department of Neurological Surgery, University of Wisconsin, Clinical Science Center, 600 Highland Ave, Box 8660, Madison, WI, 53792, USA. u.wesley@neurosurgery.wisc.edu.
authors.forename: Umadevi V
authors.initials: UV
authors.lastname: Wesley
authors.affiliation: Department of Neurological Surgery, University of Wisconsin, Clinical Science Center, 600 Highland Ave, Box 8660, Madison, WI, 53792, USA.
authors.forename: James F
authors.initials: JF
authors.lastname: Hatcher
authors.affiliation: Department of Neurological Surgery, University of Wisconsin, Clinical Science Center, 600 Highland Ave, Box 8660, Madison, WI, 53792, USA.
authors.forename: Emine R
authors.initials: ER
authors.lastname: Ayvaci
authors.affiliation: Department of Neurological Surgery, University of Wisconsin, Clinical Science Center, 600 Highland Ave, Box 8660, Madison, WI, 53792, USA.
authors.forename: Abby
authors.initials: A
authors.lastname: Klemp
authors.affiliation: Department of Neurological Surgery, University of Wisconsin, Clinical Science Center, 600 Highland Ave, Box 8660, Madison, WI, 53792, USA. dempsey@neurosurgery.wisc.edu.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Dempsey
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism; D002545:Brain Ischemia / Q000201:enzymology* / Q000473:pathology; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology*; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism*; D042783:Endothelial Cells / Q000378:metabolism; D008297:Male; D009389:Neovascularization, Pathologic / Q000378:metabolism*; D058953:Neural Stem Cells / Q000201:enzymology*; D055495:Neurogenesis / Q000502:physiology; D051381:Rats; D020521:Stroke / Q000201:enzymology* / Q000628:therapy
chemical_list: C000602659:DPP4 protein, rat; D018819:Dipeptidyl Peptidase 4
keywords: Angiogenesis; Dipeptidyl peptidase IV; Ischemic brain injury; Migration; Neural progenitor cells; Stromal-derived factor