Pericyte-Specific Ninjurin1 Deletion Attenuates Vessel Maturation and Blood Flow Recovery in Hind Limb Ischemia

Minoshima, Akiho; Kabara, Maki; Matsuki, Motoki; Yoshida, Yasuhiko; Kano, Kohei; Tomita, Yoshihiro; Hayasaka, Taiki; Horiuchi, Kiwamu; Saito, Yukihiro; Aonuma, Tatsuya; Nishimura, Masato; Maruyama, Kouichi; Nakagawa, Naoki; Sawada, Jun; Takehara, Naofumi; Hasebe, Naoyuki; Kawabe, Jun‐ichi

doi:10.1161/atvbaha.118.311375

Cited by 20 publications

(48 citation statements)

References 42 publications

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“…Furthermore, as for the role of Ninj1 in regulating vascular homeostasis, Minoshima et al [89] have different findings as well. According to previous research reports, they can conclude that Ninj1 can inhibit the formation of EC tubes by reducing the nutritional effect of PCs [77].…”

Section: Discussionmentioning

confidence: 99%

“…Thus, Minoshima et al constructed a hindlimb ischemia model by using WT and PC-specific Ninj1-knockout murine. And, they disclosed that Ninj1 in PCs could promote the formation of functional vessels within the ischemic tissues, thus could promote the blood flow recovery in hindlimb ischemia via the association between PCs and ECs [89]. Intriguingly, the expression of Ninj1 is upregulated in both ischemic skeletal muscle tissue and penile tissue under diabetic conditions, whereas its role in regulating vascular homeostasis is contradictory in both states.…”

Section: Discussionmentioning

confidence: 99%

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The Role of Ninjurin1 and Its Impact beyond the Nervous System

Liu

Wang

2020

Dev Neurosci

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Ninjurin1 (Ninj1) is a double-transmembrane cell surface protein that could promote nerve regeneration in the process of the peripheral nervous system injury and repairment. Nonetheless, the accurate function of Ninj1 in the central nervous system and outside the nervous system is not completely clear. According to the recent studies, we found that Ninj1 is also aberrantly expressed in various pathophysiological processes in vivo, including inflammation, tumorigenesis, and vascular, bone, and muscle homeostasis. These findings suggest that Ninj1 may play an influential role during these pathophysiological processes. Our review summarizes the diverse roles of Ninj1 in multiple pathophysiological processes inside and outside the nervous system. Ninj1 should be considered as an important and novel therapeutic target in certain diseases, such as inflammatory diseases and ischemic diseases. Our study provided a better understanding of Ninj1 in different pathophysiological processes and thereby provided the theoretical support for further research.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

The Role of Ninjurin1 and Its Impact beyond the Nervous System

Liu

Wang

2020

Dev Neurosci

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“…However, we cannot exclude the possibility that functional blocking of the heterophilic interactions between Ninj1 and another molecule (not yet identified) also play a role or that N-NAM could act as a novel ligand for another receptor. Furthermore, because the angiogenesis-related effects of Ninj1 have been reported in cells other than endothelial cells, for example in pericytes 27,28 and macrophages 11 , it is possible that N-NAM also affects those cells. Although we failed to find any functional motif or proteins harboring sequences homologous to N-NAM in a BLAST search, additional studies are required to investigate the heterophilic interactions of Ninj1 by N-NAM and possible novel roles of N-NAM.…”

Section: Discussionmentioning

confidence: 99%

“…During early ocular development, Ninj1-overexpressing macrophages decreased Ang1 and increased Ang2 in pericytes, resulting in hyoid vessel endothelial cell apoptosis 11 . Furthermore, in hind limb ischemia animal model, Ninj1 was induced in pericytes and modulated Ang1/Ang2 expression 27 , 28 . Pericytes play a critical role during the initial endothelial cell sprouting, guiding newly formed vessel 29 .…”

Section: Discussionmentioning

confidence: 99%

“…Later, during the vascular maturation, pericytes are strongly associated with immature vessels and induces vascular stabilization and maturation 30 , 31 . Ninj1 in pericyte is involved in the vessel maturation through the association between pericytes and endothelial cells, leading to blood flow recovery from ischemia 28 . In the present study, we reported that N-NAM up- and down-regulates Ang1 and Ang2, respectively, in HUVECs and promotes vascular permeability in the postishcemic brain.…”

Section: Discussionmentioning

confidence: 99%

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Ninjurin 1 dodecamer peptide containing the N-terminal adhesion motif (N-NAM) exerts proangiogenic effects in HUVECs and in the postischemic brain

Kim

Lee

Seol

et al. 2020

Sci Rep

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Nerve injury-induced protein 1 (Ninjurin 1, Ninj1) is a cell adhesion molecule responsible for cell-to-cell interactions between immune cells and endothelial cells. In our previous paper, we have shown that Ninj1 plays an important role in the infiltration of neutrophils in the postischemic brain and that the dodecamer peptide harboring the Ninj1 N-terminal adhesion motif (N-NAM, Pro26-Asn37) inhibits infiltration of neutrophils in the postischemic brain and confers robust neuroprotective and anti-inflammatory effects. In the present study, we examinedt the pro-angiogenic effect of N-NAM using human umbilical vein endothelial cells (HUVECs) and rat MCAO (middle cerebral artery occlusion) model of stroke. We found that N-NAM promotes proliferation, migration, and tube formation of HUVECs and demonstrate that the suppression of endogenous Ninj1 is responsible for the N-NAM-mediated pro-angiogenic effects. Importantly, a pull-down assay revealed a direct binding between exogenously delivered N-NAM and endogenous Ninj1 and it is N-terminal adhesion motif dependent. In addition, N-NAM activated the Ang1-Tie2 and AKT signaling pathways in HUVECs, and blocking those signaling pathways with specific inhibitors suppressed N-NAM-induced tube formation, indicating critical roles of those signaling pathways in N-NAM-induced angiogenesis. Moreover, in a rat MCAO model, intranasal administration of N-NAM beginning 4 days post-MCAO (1.5 µg daily for 3 days) augmented angiogenesis in the penumbra of the ipsilateral hemisphere of the brain and significantly enhanced total vessel lengths, vessel densities, and pro-angiogenic marker expression. These results demonstrate that the 12-amino acid Ninj1 peptide, which contains the N-terminal adhesion motif of Ninj1, confers pro-angiogenic effects and suggest that those effects might contribute to its neuroprotective effects in the postischemic brain.

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Capillary-resident EphA7+ pericytes are multipotent cells with anti-ischemic effects through capillary formation

Yoshida

Kabara

Kano

et al. 2019

Stem Cells Translational Medicine

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The presence of pericytes (PCs) with multipotency and broad distribution along capillary suggests that microvasculature plays a role not only as a duct for blood fluid transport but also as a stem cell niche that contributes to tissue maintenance and regeneration. The lack of an appropriate marker for multipotent PCs still limits our understanding of their pathophysiological roles. We identified the novel marker EphA7 to detect multipotent PCs using microarray analysis of an immortalized PC library. PCs were isolated from microvessels of mouse subcutaneous adipose tissues, then EphA7 + PCs called capillary stem cells (CapSCs) were separated from EphA7 − control PCs (ctPCs) using fluorescence-activated cell sorting system. CapSCs had highly multipotency that enabled them to differentiate into mesenchymal and neuronal lineages compared with ctPCs. CapSCs also differentiated into endothelial cells and PCs to form capillary-like structures by themselves. Transplantation of CapSCs into ischemic tissues significantly improved blood flow recovery in hind limb ischemia mouse model due to vascular formation compared with that of ctPCs and adipose stromal cells. These data demonstrate that EphA7 identifies a subpopulation of multipotent PCs that have high angiogenesis and regenerative potency and are an attractive target for regenerative therapies.

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Pericyte-Specific Ninjurin1 Deletion Attenuates Vessel Maturation and Blood Flow Recovery in Hind Limb Ischemia

Abstract: Supplemental Digital Content is available in the text.

Cited by 20 publications

References 42 publications

The Role of Ninjurin1 and Its Impact beyond the Nervous System

The Role of Ninjurin1 and Its Impact beyond the Nervous System

Ninjurin 1 dodecamer peptide containing the N-terminal adhesion motif (N-NAM) exerts proangiogenic effects in HUVECs and in the postischemic brain

Capillary-resident EphA7+ pericytes are multipotent cells with anti-ischemic effects through capillary formation

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