Neuropilin-1 modulates vascular endothelial growth factor-induced poly(ADP-ribose)-polymerase leading to reduced cerebrovascular apoptosis

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 V-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.

Neuropilin-1 assists SARS-CoV-2 infection by stimulating the separation of Spike protein S1 and S2

“…Thus, the Spike protein binding with Nrp1 may directly or indirectly interfere with the formation of the endogenous receptor complex, with its signaling and functions in the host cell (12)(13)(14). This connection between the SARS-CoV-2 Spike protein and neuropilin may relate the longer-term effects of COVID-19 on the biological processes in neurons and blood vessels (15)(16)(17). Specifically, a significant number of critically ill COVID-19 patients experience impairments such as brain inflammation, an increased permeability of the bloodbrain barrier, as well as an elevated occurrence in the number of strokes (18)(19)(20)(21).…”

Neuropilin-1 promotes mitochondrial structural repair and functional recovery in rats with cerebral ischemia

“…NRP-1 has been documented in neurons, T-cells, dendritic cells and migrating cancer cells [ 39 – 41 ]. A previous study has reported an increased expression of endothelial NRP-1 in the ischemic cerebral hemispheres, which helped to prevent the cellular damage in cerebrovascular diseases [ 42 ]. Data suggest that NRP-1 in the endothelial cells is up-regulated and contributes to neovascularization in post-ischemia brain [ 43 ].…”

Morroniside Improves Microvascular Functional Integrity of the Neurovascular Unit after Cerebral Ischemia

“…FGF-2, one of the first discovered angiogenic factors, mediates vessel growth by stimulating the release of VEGF and other signaling, and is required for the maintenance of vascular integrity [50]. NRP-1, expressed in neurons, vessels and astrocytes, also has angiogenic properties, identified as co-receptors for VEGF or to form complexes with VEGFR [51]. It has also been reported to be increased by FGF-2 to enhance vascular smooth muscle cell migration, besides guidance of endothelial tip cell [52].…”