Universität zu Köln

Mey, Lilli, Hoermann, Mareike, Schleicher, Nadine, Reuter, Peter, Doenges, Simone, Kinscherf, Ralf, Gassmann, Max, Gerriets, Tibo and Al-Fakhri, Nadia (2013). Neuropilin-1 modulates vascular endothelial growth factor-induced poly(ADP-ribose)-polymerase leading to reduced cerebrovascular apoptosis. Neurobiol. Dis., 59. S. 111 - 126. SAN DIEGO: ACADEMIC PRESS INC ELSEVIER SCIENCE. ISSN 1095-953X

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Abstract

Cerebral ischemia is encompassed by cerebrovascular apoptosis, yet the mechanisms behind apoptosis regulation are not fully understood. We previously demonstrated inhibition of endothelial apoptosis by vascular endothelial growth factor (VEGF) through upregulation of poly(ADP-ribose)-polymerase (PARP) expression. However, PARP overactivation through oxidative stress can lead to necrosis. This study tested the hypothesis that neuropilin-1 (NP-1), an alternative VEGF receptor, regulates the response to cerebral ischemia by modulating PARP expression and, in turn, apoptosis inhibition by VEGF. In endothelial cell culture, NP-1 colocalized with VEGF receptor-2 (VEGFR-2) and acted as its coreceptor. This significantly enhanced VEGF-induced PARP mRNA and protein expression demonstrated by receptor-specific inhibitors and VEGF-A isoforms. NP-1 augmented the inhibitory effect of VEGF/VEGFR-2 interaction on apoptosis induced by adhesion inhibition through the alpha N-integrin inhibitor cRGDfV. NP-1/VEGFR-2 signal transduction involved JNK and Akt In rat models of permanent and temporary middle cerebral artery occlusion, the ischemic cerebral hemispheres displayed endothelial and neuronal apoptosis next to increased endothelial NP-1 and VEGFR-2 expression compared to non-ischemic cerebral hemispheres, sham-operated or untreated controls. Increased vascular superoxide dismutase-1 and catalase expression as well as decreased glycogen reserves indicated oxidative stress in the ischemic brain. Of note, protein levels of intact PARP remained stable despite pro-apoptotic conditions through increased PARP mRNA production during cerebral ischemia. In conclusion, NP-1 is upregulated in conditions of imminent cerebrovascular apoptosis to reinforce apoptosis inhibition and modulate VEGF-dependent PARP expression and activation. We propose that NP-1 is a key modulator of VEGF maintaining cerebrovascular integrity during ischemia. Modulating the function of NP-1 to target PARP could help to prevent cellular damage in cerebrovascular disease. (C) 2013 Elsevier Inc. All rights reserved.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Mey, Lilli UNSPECIFIED UNSPECIFIED UNSPECIFIED Hoermann, Mareike UNSPECIFIED UNSPECIFIED UNSPECIFIED Schleicher, Nadine UNSPECIFIED UNSPECIFIED UNSPECIFIED Reuter, Peter UNSPECIFIED UNSPECIFIED UNSPECIFIED Doenges, Simone UNSPECIFIED UNSPECIFIED UNSPECIFIED Kinscherf, Ralf UNSPECIFIED UNSPECIFIED UNSPECIFIED Gassmann, Max UNSPECIFIED UNSPECIFIED UNSPECIFIED Gerriets, Tibo UNSPECIFIED UNSPECIFIED UNSPECIFIED Al-Fakhri, Nadia UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-473033
DOI:	10.1016/j.nbd.2013.06.009
Journal or Publication Title:	Neurobiol. Dis.
Volume:	59
Page Range:	S. 111 - 126
Date:	2013
Publisher:	ACADEMIC PRESS INC ELSEVIER SCIENCE
Place of Publication:	SAN DIEGO
ISSN:	1095-953X
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language CEREBRAL-ARTERY OCCLUSION; UP-REGULATION; FACTOR EXPRESSION; FACTOR RECEPTOR-2; BRAIN GLYCOGEN; VEGF; CELL; INDUCTION; ISCHEMIA; STROKE Multiple languages Neurosciences Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/47303