• BMB Reports
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• 제41권5호
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• pp.345-352
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• 2008

The cerebral microvessels possess barrier characteristics which are tightly sealed excluding many toxic substances and protecting neural tissues. The specialized blood-neural barriers as well as the cerebral microvascular barrier are recognized in the retina, inner ear, spinal cord, and cerebrospinal fluid. Microvascular endothelial cells in the brain closely interact with other components such as astrocytes, pericytes, perivascular microglia and neurons to form functional 'neurovascular unit'. Communication between endothelial cells and other surrounding cells enhances the barrier functions, consequently resulting in maintenance and elaboration of proper brain homeostasis. Furthermore, the disruption of the neurovascular unit is closely involved in cerebrovascular disorders. In this review, we focus on the location and function of these various blood-neural barriers, and the importance of the cell-to-cell communication for development and maintenance of the barrier integrity at the neurovascular unit. We also demonstrate the close relation between the alteration of the blood-neural barriers and cerebrovascular disorders.

• BMB Reports
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• 제51권2호
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• pp.65-72
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• 2018

The endothelial to mesenchymal transition (EndMT) is a newly recognized, fundamental biological process involved in development and tissue regeneration, as well as pathological processes such as the complications of diabetes, fibrosis and pulmonary arterial hypertension. The EndMT process is tightly controlled by diverse signaling networks, similar to the epithelial to mesenchymal transition. Accumulating evidence suggests that microRNAs (miRNAs) are key regulators of this network, with the capacity to target multiple messenger RNAs involved in the EndMT process as well as in the regulation of disease progression. Thus, it is highly important to understand the molecular basis of miRNA control of EndMT. This review highlights the current fund of knowledge regarding the known links between miRNAs and the EndMT process, with a focus on the mechanism that regulates associated signaling pathways and discusses the potential for the EndMT as a therapeutic target to treat many diseases.

• The Korean Journal of Physiology and Pharmacology
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• 제19권4호
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• pp.335-340
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• 2015

Here, we investigated the role of zerumbone, a natural cyclic sesquiterpene of Zingiber zerumbet Smith, on angiogenesis using human umbilical vein endothelial cells (HUVECs). Zerumbone inhibited HUVECs proliferation, migration and tubule formation, as well as angiogenic activity by rat aorta explants. In particular, zerumbone inhibited phosphorylation of vascular endothelial growth factor receptor-2 and fibroblast growth factor receptor-1, which are key regulators of endothelial cell function and angiogenesis. In vivo matrigel plug assay in mice demonstrated significant decrease in vascularization and hemoglobin content in the plugs from zerumbone-treated mice, compared with control mice. Overall, these results suggest that zerumbone inhibits various attributes of angiogenesis, which might contribute to its reported antitumor effects.

• Archives of Plastic Surgery
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• 제36권4호
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• pp.380-384
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• 2009

Purpose: Autologous vessels remain the gold standard for vascular grafts in microanastomoses. However, they are sometimes unavailable and have a limited long - term patency. Synthetic vessels have high success rates in large - diameter reconstructions but failed when used as small - diameter grafts due to graft occlusion. It has been proved that endothelial cell seeding improves prosthesis performance and long - term patency. Among polyurethane, PET and ePTFE, polyurethane has the best affinity to endothelial cells and mechanical properties closest to human vessels. We examined the ability of endothelial cells to attach to a polyurethane graft manufactured by the electrospinning method. Methods: Endothelial cells, which were cultured from porcine internal jugular veins, were attached to polyurethane grafts with an internal diameter of 3 mm. The same cells were attached to allogeneic decellularized porcine internal carotid artery grafts as controls. Both of the 10 mm - long grafts were exposed to endothelial cells in a well for 1 hour. Each well contained $2{\times}10^5$ endothelial cells. The graft materials were rotated through 90 degrees every 15 minutes in order to minimize the effect of gravity. The extent of cell attachment was examined with the MTT assay. Results: The MTT assay showed good incorporation of endothelial cells into both grafts. For the evaluation of affinity, the number of attached cells was counted at 10 fields of microscopic examination with ${\times}40$ magnification. Endothelial cells adhered more to polyurethane grafts (mean, $127.4{\pm}6.2cells$) compared to porcine artery grafts (mean $45.8{\pm}5.1cells$)(p<0.05,Mann - Whitney test). Conclusion: In this study, we attached porcine endothelial cells to polyurethane grafts, manufactured by electrospinning. The grafts exhibited a better affinity to endothelial cells than allogeneic decellularized porcine internal carotid artery grafts. It is suggested that the time required for endothelial cells to attach to decellulized artery grafts may be longer than that which is required for attachment to polyurethane grafts.

• Journal of Ginseng Research
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• 제47권1호
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• pp.144-154
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• 2023

Background: As the major pathophysiological feature of obstructive sleep apnea (OSA), chronic intermittent hypoxia (CIH) is vital for the occurrence of cardiovascular complications. The activation of calpain-1 mediates the production of endothelial reactive oxygen species (ROS) and impairs nitric oxide (NO) bioavailability, resulting in vascular endothelial dysfunction (VED). Ginsenoside Rg1 is thought to against endothelial cell dysfunction, but the potential mechanism of CIH-induced VED remains unclear. Methods: C57BL/6 mice and human coronary artery endothelial cells (HCAECs) were exposed to CIH following knockout or overexpression of calpain-1. The effect of ginsenoside Rg1 on VED, oxidative stress, mitochondrial dysfunction, and the expression levels of calpain-1, PP2A and p-eNOS were detected both in vivo and in vitro. Results: CIH promoted VED, oxidative stress and mitochondrial dysfunction accompanied by enhanced levels of calpain-1 and PP2A and reduced levels of p-eNOS in mice and cellular levels. Ginsenoside Rg1, calpain-1 knockout, OKA, NAC and TEMPOL treatment protected against CIH-induced VED, oxidative stress and mitochondrial dysfunction, which is likely concomitant with the downregulated protein expression of calpain-1 and PP2A and the upregulation of p-eNOS in mice and cellular levels. Calpain-1 overexpression increased the expression of PP2A, reduced the level of p-eNOS, and accelerated the occurrence and development of VED, oxidative stress and mitochondrial dysfunction in HCAECs exposed to CIH. Moreover, scavengers of O₂^·-, H₂O₂, complex I or mitoKATP abolished CIH-induced impairment in endothelial-dependent relaxation. Conclusion: Ginsenoside Rg1 may alleviate CIH-induced vascular endothelial dysfunction by suppressing the formation of mitochondrial reactive oxygen species through the calpain-1 pathway.

• BMB Reports
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• 제40권3호
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• pp.439-443
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• 2007

Tumor growth and metastasis are dependent on angiogenesis, and endothelial cell invasion and migration are apparent means of regulating tumor progression. We report here that saxatilin, a snake venom-derived disintegrin, suppresses the angiogenesis-inducing properties of NCI-H460 human lung cancer cells. Culture supernatants of NCI-H460 cells are able to induce human umbilical vascular endothelial cell (HUVEC) invasion and tube formation. However, treatment of the cancer cells with saxatilin resulted in reduced angiogenic activity of the culture supernatant. This suppressed angiogenic property was found to be associated with the level of vascular endothelial growth factor (VEGF) in the culture supernatant. Further experimental evidence indicated that saxatilin inhibits VEGF production in NCI-H460 cells by affecting hypoxia induced factor-1$\alpha$ (HIF-1$\alpha$) expression via the Akt pathway.

• Molecules and Cells
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• 제38권12호
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• pp.1064-1070
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• 2015

Translocator protein 18 kDa (TSPO) is a mitochondrial outer membrane protein and is abundantly expressed in a variety of organ and tissues. To date, the functional role of TSPO on vascular endothelial cell activation has yet to be fully elucidated. In the present study, the phorbol 12-myristate 13-acetate (PMA, 250 nM), an activator of protein kinase C (PKC), was used to induce vascular endothelial activation. Adenoviral TSPO overexpression (10-100 MOI) inhibited PMA-induced vascular cell adhesion molecule-1 (VCAM-1) and intracellular cell adhesion molecule-1 (ICAM-1) expression in a dose dependent manner. PMA-induced VCAM-1 expressions were inhibited by Mito-TEMPO ($0.1-0.5{\mu}m$), a specific mitochondrial antioxidants, and cyclosporin A ($1-5{\mu}m$), a mitochondrial permeability transition pore inhibitor, implying on an important role of mitochondrial reactive oxygen species (ROS) on the endothelial activation. Moreover, adenoviral TSPO overexpression inhibited mitochondrial ROS production and manganese superoxide dismutase expression. On contrasts, gene silencing of TSPO with siRNA increased PMA-induced VCAM-1 expression and mitochondrial ROS production. Midazolam ($1-50{\mu}m$), TSPO ligands, inhibited PMA-induced VCAM-1 and mitochondrial ROS production in endothelial cells. These results suggest that mitochondrial TSPO can inhibit PMA-induced endothelial inflammation via suppression of VCAM-1 and mitochondrial ROS production in endothelial cells.

• 생명과학회지
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• 제24권4호
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• pp.337-342
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• 2014

Resveratrol (RSV)은 천연 폴리페놀계 화합물로 세포분열, 성장, 세포이동 등과 같은 다양한 효과가 보고되었다. Angiogenin (ANG)은 Vascular endothelial growth factor (VEGF)와 함께 세포의 증식, 신생혈관형성, tubular structures의 형성, 세포이동 등을 이끄는 중요한 단백질이다. 본 연구에서는 RSV에 의한 세포이동효과를 HeLa 세포에서 관찰하였다. Real-time PCR을 통해 HeLa 세포에 RSV $0{\sim}50{\mu}M$을 24시간 동안 처리하였을 때, 농도에 따른 ANG, VEGF 유전자 발현이 의미 있게 증가 하였다. 같은 방법으로, RSV $50{\mu}M$을 시간에 따라(0~48시간) 처리하여 실험하였다. 그 결과, RSV $50{\mu}M$을 24시간 동안 처리하였을 때 ANG, VEGF 유전자 발현이 가장 높게 증가하였고, ANG 단백질 분석에서도 동일한 결과를 얻었다. 또한, MTT assay를 이용한 세포 독성연구에서, RSV $50{\mu}M$의 농도에서는 영향을 미치지 않음을 관찰하여, 이를 최적의 조건으로 결정하였다. RSV가 처리된 세포에서 세포이동효과를 조사하기 위해 wound-healing assay를 수행하였다. RSV가 처리된 그룹에서 세포이동이 의미 있게 증가하였다. 따라서, 본 연구에는 RSV에 의해 ANG, VEGF의 발현이 증가했고, 이에 따라 세포이동이 향상됨을 관찰하였다.

• The Korean Journal of Physiology and Pharmacology
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• 제22권2호
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• pp.203-213
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• 2018

Tumor undergo uncontrolled, excessive proliferation leads to hypoxic microenvironment. To fulfill their demand for nutrient, and oxygen, tumor angiogenesis is required. Endothelial progenitor cells (EPCs) have been known to the main source of angiogenesis because of their potential to differentiation into endothelial cells. Therefore, understanding the mechanism of EPC-mediated angiogenesis in hypoxia is critical for development of cancer therapy. Recently, mitochondrial dynamics has emerged as a critical mechanism for cellular function and differentiation under hypoxic conditions. However, the role of mitochondrial dynamics in hypoxia-induced angiogenesis remains to be elucidated. In this study, we demonstrated that hypoxia-induced mitochondrial fission accelerates EPCs bioactivities. We first investigated the effect of hypoxia on EPC-mediated angiogenesis. Cell migration, invasion, and tube formation was significantly increased under hypoxic conditions; expression of EPC surface markers was unchanged. And mitochondrial fission was induced by hypoxia time-dependent manner. We found that hypoxia-induced mitochondrial fission was triggered by dynamin-related protein Drp1, specifically, phosphorylated DRP1 at Ser637, a suppression marker for mitochondrial fission, was impaired in hypoxia time-dependent manner. To confirm the role of DRP1 in EPC-mediated angiogenesis, we analyzed cell bioactivities using Mdivi-1, a selective DRP1 inhibitor, and DRP1 siRNA. DRP1 silencing or Mdivi-1 treatment dramatically reduced cell migration, invasion, and tube formation in EPCs, but the expression of EPC surface markers was unchanged. In conclusion, we uncovered a novel role of mitochondrial fission in hypoxia-induced angiogenesis. Therefore, we suggest that specific modulation of DRP1-mediated mitochondrial dynamics may be a potential therapeutic strategy in EPC-mediated tumor angiogenesis.

• International Journal of Oncology
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• 제54권4호
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• pp.1327-1336
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• 2019

Endothelial progenitor cells (EPCs) are bone marrow (BM)-derived progenitor cells that can differentiate into mature endothelial cells, contributing to vasculogenesis in the blood vessel formation process. Runt-related transcription factor 3 (RUNX3) belongs to the Runt domain family and is required for the differentiation of specific immune cells and neurons. The tumor suppressive role of RUNX3, via the induction of apoptosis and cell cycle arrest in a variety of cancers, and its deletion or frequent silencing by epigenetic mechanisms have been studied extensively; however, its role in the differentiation of EPCs is yet to be investigated. Therefore, in the present study, adult BM-derived hematopoietic stem cells (HSCs) were isolated from Runx3 heterozygous (Rx3^+/-) or wild-type (WT) mice. The differentiation of EPCs from the BM-derived HSCs of Rx3^+/- mice was found to be significantly increased compared with those of the WT mice, as determined by the number of small or large colony-forming units. The migration and tube formation abilities of Rx3^+/- EPCs were also observed to be significantly increased compared with those of WT EPCs. Furthermore, the number of circulating EPCs, defined as CD34⁺/vascular endothelial growth factor receptor 2 (VEGFR2)⁺ cells, was also significantly increased in Rx3^+/- mice. Hypoxia-inducible factor (HIF)-1α was upregulated in Rx3^+/- EPCs compared with WT EPCs, even under normoxic conditions. Furthermore, in a hindlimb ischemic mouse models, the recovery of blood flow was observed to be highly stimulated in Rx3^+/- mice compared with WT mice. Also, in a Lewis lung carcinoma cell allograft model, the tumor size in Rx3^+/- mice was significantly larger than that in WT mice, and the EPC cell population (CD34⁺/VEGFR2⁺ cells) recruited to the tumor was greater in the Rx3^+/- mice compared with the WT mice. In conclusion, the present study revealed that Runx3 inhibits vasculogenesis via the inhibition of EPC differentiation and functions via the suppression of HIF-1α activity.