• BMB Reports
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• v.55 no.11
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• pp.565-570
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• 2022

Pulmonary arterial hypertension (PAH) is a progressive and devastating disease whose pathogenesis is associated with a phenotypic switch of pulmonary arterial vascular smooth muscle cells (PASMCs). Bone morphogenetic protein (BMP) signaling and potassium two pore domain channel subfamily K member 3 (KCNK3) play crucial roles in PAH pathogenesis. However, the relationship between BMP signaling and KCNK3 expression in the PASMC phenotypic switching process has not been studied. In this study, we explored the effect of BMPs on KCNK3 expression and the role of KCNK3 in the BMP-mediated PASMC phenotypic switch. Expression levels of BMP receptor 2 (BMPR2) and KCNK3 were downregulated in PASMCs of rats with PAH compared to those in normal controls, implying a possible association between BMP/BMPR2 signaling and KCNK3 expression in the pulmonary vasculature. Treatment with BMP2, BMP4, and BMP7 significantly increased KCNK3 expression in primary human PASMCs (HPASMCs). BMPR2 knockdown and treatment with Smad1/5 signaling inhibitor substantially abrogated the BMP-induced increase in KCNK3 expression, suggesting that KCNK3 expression in HPASMCs is regulated by the canonical BMP-BMPR2-Smad1/5 signaling pathway. Furthermore, KCNK3 knockdown and treatment with a KCNK3 channel blocker completely blocked BMP-mediated anti-proliferation and expression of contractile marker genes in HPAMSCs, suggesting that the expression and functional activity of KCNK3 are required for BMP-mediated acquisition of the quiescent PASMC phenotype. Overall, our findings show a crosstalk between BMP signaling and KCNK3 in regulating the PASMC phenotype, wherein BMPs upregulate KCNK3 expression and KCNK3 then mediates BMP-induced phenotypic switching of PASMCs. Our results indicate that the dysfunction and/or downregulation of BMPR2 and KCNK3 observed in PAH work together to induce aberrant changes in the PASMC phenotype, providing insights into the complex molecular pathogenesis of PAH.

• Journal of Life Science
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• v.32 no.2
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• pp.175-188
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• 2022

Relaxin has been demonstrated to have regulatory functions on both the smooth muscle and extracellular matrix (ECM) of blood vessels and fibrotic organs. The diverse mechanisms by which relaxin acts on small resistance arteries and fibrotic organs, including the bladder, are reviewed here. Relaxin induces vasodilation by inhibiting the contractility of vascular smooth muscles and by increasing the passive compliance of vessel walls through the reduction of ECM components, such as collagen. The primary cellular mechanism whereby relaxin induces arterial vasodilation is mediated by the endothelium-dependent production of nitric oxide (NO) through the activation of RXFP1/PI3K, Akt phosphorylation, and eNOS. In addition, relaxin triggers different alternative pathways to enhance the vasodilation of renal and mesenteric arteries. In small renal arteries, relaxin stimulates the activation of the endothelial MMPs and EtB receptors and the production of VEGF and PlGF to inhibit myogenic contractility and collagen deposition, thereby bringing about vasodilation. Conversely, in small mesenteric arteries, relaxin augments bradykinin (BK)-evoked relaxation in a time-dependent manner. Whereas the rapid enhancement of the BK-mediated relaxation is dependent on IK_Ca channels and subsequent EDH induction, the sustained relaxation due to BK depends on COX activation and PGI₂. The anti-fibrotic effects of relaxin are mediated by inhibiting the invasion of inflammatory immune cells, the endothelial-to-mesenchymal transition (EndMT), and the differentiation and activation of myofibroblasts. Relaxin also activates the NOS/NO/cGMP/PKG-1 pathways in myofibroblasts to suppress the TGF-β1-induced activation of ERK1/2 and Smad2/3 signaling and deposition of ECM collagen.

• Journal of Korean Neurosurgical Society
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• v.67 no.2
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• pp.146-157
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• 2024

Objective : Chronic subdural hematomas (cSDHs) are generally known to result from traumatic tears of bridging veins. However, the causes of repeat spontaneous cSDHs are still unclear. We investigated the changes in vasculature in the human dura mater and outer membrane (OM) of cSDHs to elucidate the cause of their spontaneous repetition. Methods : The dura mater was obtained from a normal control participant and a patient with repeat spontaneous cSDHs. The pathological samples from the patient included the dura mater and OM tightly adhered to the inner dura. The samples were analyzed with a particular focus on blood and lymphatic vessels by immunohistochemistry, 3-dimensional imaging using a transparent tissue clearing technique, and electron microscopy. Results : The dural border cell (DBC) layer of the dura mater and OM were histologically indistinguishable. There were 5.9 times more blood vessels per unit volume of tissue in the DBC layer and OM in the patient than in the normal control. The DBC layer and OM contained pathological sinusoidal capillaries not observed in the normal tissue; these capillaries were connected to the middle meningeal arteries via penetrating arteries. In addition, marked lymphangiogenesis in the periosteal and meningeal layers was observed in the patient with cSDHs. Conclusion : Neovascularization in the OM seemed to originate from the DBC layer; this is a potential cause of repeat spontaneous cSDHs. Embolization of the meningeal arteries to interrupt the blood supply to pathological capillaries via penetrating arteries may be an effective treatment option.

• Journal of Life Science
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• v.34 no.6
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• pp.418-425
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• 2024

Solid tumors are heterogeneous populations of multiple cell types. While the majority of the cells that comprise cancer are unable to divide, cancer stem cells have self-renewal and differentiation properties. Normal stem cell pathways that control self-renewal are overactivated in cancer stem cells, making cancer stem cells important for cancer cell expansion and progression. Dick first proposed the definition of cancer stem cells in acute myeloid leukemia, according to which cancer stem cells can be classified based on the expression of cell surface markers. Cancer stem cells maintain their potential in the tumor microenvironment. Multiple cell types in the tumor microenvironment maintain quiescent cancer stem cells and serve as regulators of cancer growth. Since current cancer treatments target proliferative cells, quiescent state cancer stem cells that are resistant to treatment increase the risk of recurrence or metastasis. Various signals of the tumor microenvironment induce changes to become a tumor-supportive environment by remodeling the vasculature and extracellular matrix. To effectively treat cancer, cancer stem cells and the tumor microenvironment must be targeted. Therefore, it is important to understand how the tumor microenvironment induces reprogramming of the immune response to promote cancer growth, immune resistance, and metastasis. In this review, we discuss the cellular and molecular mechanisms that can enhance immunosuppression in the tumor microenvironment.

• Clinical and Experimental Pediatrics
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• v.50 no.11
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• pp.1078-1084
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• 2007

Purpose : The prevalence of childhood obesity has doubled over the last 30 years. Obesity-associated sequelae in the vasculature begins in the early stages of life. The purpose of this study was to investigate how pulse wave velocity (PWV) and ankle brachial index (ABI) change with height, weight and body mass index (BMI) in obese adolescents. Methods : Seventy-nine obese adolescents (group 1: $85th{\leq}BMI<95th$ percentile, n=40; group 2 ($BMI{\geq}95th$ percentile, n=39) were included. The control group(group 3) included 99 healthy adolescents. Brachial- ankle (ba) PWV and ABI were estimated with blood pressure from four extremities. Heart rate (HR), and pre-ejection period/ejection time (PEP/ET) were also estimated. BMI was calculated from individual height and weight. Linear regression analysis was performed to evaluate the correlations between BMI and PWV. Results : Blood pressure and baPWV were significantly higher in group 2, compared to either group 1 or group 3. However, there was no significant difference in ABI, HR and PEP/ET between the groups. PWV showed linear correlation with both BMI and body weight. Conclusion : Obesity was associated with higher arterial stiffness in adolescents, which was demonstrated by an increase in PWV. There was no significant correlation between obesity and ABI.

• Archives of Reconstructive Microsurgery
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• v.5 no.1
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• pp.24-34
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• 1996

There are many kinds of free flaps for management of extensive soft tissue defect of extremities in orthopaedic field. Free vascularized scapular flap is one of the most useful and relatively easy to application. This flap has been utilize clinically from early eighties by many microsurgical pioneers. Authors performed 102 cases of this flap from 1984 to 1995. We have to consider about the surgical anatomy of the flap, technique of the donor harvesting procedures, vascular varieties and anatomical abnormalities and success rate and the weak points of the procedure. This flap nourished by cutaneous branches from circumflex scapular vessels emerges from the lateral aspect of the subscapular artery 2.5-5cm from its lateral origin passing through the triangular space(bounded by subscapularis, teres minor, teres major, long head of triceps). The terminal cutaneous branch runs posteriorly around the lateral border of the scapular and divided into two major branches, those transeverse horizontally and obliquely to the fascial plane of overlying skin of the scapular body. We can utilize these arteries for scapular and parascapular flap. The vascular pedicle ranged from 5 to 10 cm long depends on the dissection, usually two venae comitantes accompanied circumflex scapular artery and its major branches. The diameter of the circumflex scapular artery is more than 1mm in adult, rare vascular variation. Surgical techniques : The scapular flap can be dissected conveniently with prone or lateral decubitus position, prone position is more easier in my experience. There are two kinds of surgical approaches, most of the surgeon prefer elevation of the flap from its outer border towards its base which known easier and quicker, but I prefer elevation of the flap from its outer border because of the lowering the possibilities of damage to vasculature in the flap itself which runs just underneath the subcutaneous tissue of the flap and provide more quicker elevation of the flap with blunt finger dissection after secure pedicle dissection and confirmed the course from the base of the pedicle. There are minimal donor site morbidity with direct skin closure if the flap size is not so larger than 10cm width. This flap has versatility in the design of the flap shape and size, if we need more longer and larger one, we can use parascapular flap or both. Even more, the flap can be used with latissimus dorsi musculocutaneous flap and serratus anterior flap which have common vascular pedicle from subscapular artery, some instance can combined with osteocutaneous flap if we include the lateral border of the scapular bone or parts of the ribs with serratus anterior. The most important shortcoming of the scapular free flap is non sensating, there are no reasonable sensory nerves to the flap to anastomose with recipient site nerve. Results : Among our 102 cases, overall success rate was 89%, most of the causes of the failure was recipient site vascular problems such as damaged recipient arterial conditions, and there were two cases of vascular anomalies in our series. Patients ages from 3 years old to 62 years old. Six cases of combined flap with latissimus dorsi, 4 cases of osteocutaneous flap for bone reconstruction, 62 parascapular flap was performed - we prefer parascapular flap to scapular. Statistical analysis of the size of the flap has less meaningful because of the flap has great versatility in size. In the length of the pedicle depends on the recipient site condition, we can adjust the pedicle length. The longest vascular pedicle was 14 cm in length from the axillary artery to the enter point cutaneous tissue. In conclusion, scapular free flap is one of the most useful modalities to manage the large intractable soft tissue defect. It has almost constant vascular pedicle with rare anatomical variation, easy to dissect great versatility in size and shape, low donor morbidity, thin and hairless skin.

• Investigative Magnetic Resonance Imaging
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• v.8 no.1
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• pp.17-23
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• 2004

Purpose : To evaluate changes in total cerebral blood flow (tCBF) with aging, parenchymal volume changes and vascular abnormalities, using 2 dimensional (D) phase-contrast magnetic resonance imaging (PC MRI). Materials and Methods : Routine brain MRI including T2 weighted image, time-of-flight (TOF) MR Angiography (MRA) and 2D PC MRI were performed in 73 individuals, including 12 volunteers. Normal subjects (12 volunteers, and 21 individuals with normal MRI and normal MRA) were classified into groups according to age (18-29, 30-49 and 50-66 years). For the group with abnormalities in brain MRIs, cerebral parenchymal volume changes were scored according to the T2 weighted images, and atherosclerotic changes were scored according to the MRA findings. Abnormal groups were classified into 4 groups: (i) mild reduction in volume, (ii) marked reduction in volume by parenchymal volume and atherosclerotic changes, and (iii) increased volume and (iv) Moya-moya disease. Volumetric flow was measured at the internal carotid artery (ICA) and vertebral artery bilaterally using the velocity-flow diagrams from PC MRI, and combined 4 vessel flows and tCBF were compared among all the groups. Results : The age-specific distribution of tCBFs in normal subjects were as follows: $12.0{\pm}2.1ml/sec$ in 18-29 years group, $11.8{\pm}1.9ml/sec$ in 30-49 years group, $10.9{\pm}2.2ml/sec$ in 50-66 years group. The distribution of tCBFs in the different subsets of the abnormal population were as follows: $9.5{\pm}2.5ml/sec$ in the group with mild reduction in volume, $7.6{\pm}2.0ml/sec$ in the group with marked reduction in volume, and $7.3{\pm}1.2ml/sec$ and $7.0{\pm}1.1ml/sec$ in the increased parenchymal volume and Moya-moya disease groups respectively. Conclusion : Total cerebral blood flow decreases with increasing age with a concomitant reduction in parenchymal volumes and increasing atherosclerotic changes. It is also reduced in the presence of increased parenchymal volume and Moya-moya disease.2D PC MRI can be used as a tool to evaluate tCBF with aging and in the presence of various conditions that can affect parenchymal volume and cerebral vasculature.

• Investigative Magnetic Resonance Imaging
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• v.9 no.2
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• pp.94-100
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• 2005

Purpose : This study was designed to evaluate the usefulness of 3T-TOF MR angiography (3T-TOF MRA) compared with transcranial Doppler sonography (TCD) and conventional angiography (CA) in patients with suspected cerebral infarction. Materials and Methods : Fifty four patients with clinical symptoms of cerebral infarction were involved in this study, and had undergone 3T-TOF MRA and TCD, with CA in 11 patients. On the basis of divisions of the carotid artery, four groups were designated: group I, both vertebral arteries and basilar artery; group II, segment between 2 cm below bifurcation of common carotid artery and genu portion of internal carotid artery; group III, segment between petrous portion of internal carotid artery and bifurcation of anterior and middle cerebral artery; group IV, from bifurcation of anterior and middle cerebral artery to thier distal branches. Two radiologists retrospectively reviewed the vascular imaging and stenosis in 3T-TOF MRA, TCD, and CA. Results : A total of 432 arteries, 108 in each group, were available. The assessment of vascular imaging quality in 3T-TOF MRA is scored 2.98, 2.96, 2.91, 2.88 in 4 groups, respectively. Agreement among 3T-TOF MR angiography, TCD, and CA was high. Conclusion : 3T-TOF MR angiography may be useful method for the assessment of stenotic lesions of cranial vasculature in patients with cerebral infarction.