Background and aims: One of the primary causes of lumen narrowing is vascular injury induced during medical procedures. Vascular injury disrupts the integrity of the endothelium, triggering platelet deposition, leukocyte recruitment, and the release of inflammatory factors. This, in turn, induces the proliferation of vascular smooth muscle cells (VSMCs), leading to neointima formation. However, the molecular mechanism underlying VSMC proliferation following injury remains unknown. KIF11 is critical in regulating the cell cycle by forming bipolar spindles during mitotic metaphase. This process may contribute to VSMCs proliferation and neointima formation following vascular injury. Yet, the function of KIF11 in VSMCs has not been elucidated. This study aims to investigate the role and mechanisms of KIF11 in regulating VSMCs cycle progression and proliferation. Methods: After conducting biological analysis of the transcriptome sequencing data from the mouse carotid artery injury model and the cell transcriptome data of PDGF-BB-induced VSMCs, we identified a potential target gene, KIF11, which may play a crucial role in vascular injury. Then we established a vascular injury model to investigate how changes in KIF11 expression and activity influence in vivo VSMCs proliferation and neointimal formation. In addition, we employed siRNA and specific inhibitors to suppress KIF11 expression and activity in VSMCs cultured in vitro to study the mechanisms underlying VSMCs cycle progression and proliferation. Results: The results of immunohistochemistry and immunofluorescence indicate a significant upregulation of KIF11 expression in the injured vascular. The intraperitoneal injection of the KIF11 specific inhibitor, K858, partially inhibits intimal hyperplasia in the vascular injury model. In vitro experiments further demonstrate that PDGF-BB upregulates KIF11 expression through the PI3K/AKT pathway, and enhances KIF11 activity. Inhibition of both KIF11 expression and activity partially reverses the pro-cycle progression and pro-proliferation effects of PDGF-BB on VSMCs. Additionally, KIF11 overexpression partially counteracts the proliferation arrest and cell cycle arrest induced by inhibiting the PI3K/AKT pathway in VSMCs. Conclusion: Our study highlights the crucial role of KIF11 in regulating the cycle progression and proliferation of VSMCs after vascular injury. A comprehensive understanding of these mechanisms could pave the way for potential therapeutic interventions in treating vascular stenosis.

Dysbiosis of the gut microbiota has been implicated in hypertension, and drug-host-microbiome interactions have drawn considerable attention. However, the influence of angiotensin receptor blocker (ARB)-shaped gut microbiota on the host is not fully understood. In this work, we assessed the alterations of blood pressure (BP), vasculatures, and intestines following ARB-modified gut microbiome treatment and evaluated the changes in the intestinal transcriptome and serum metabolome in hypertensive rats. Hypertensive patients with well-controlled BP under ARB therapy were recruited as human donors, spontaneously hypertensive rats (SHRs) receiving normal saline or valsartan were considered animal donors, and SHRs were regarded as recipients. Histological and immunofluorescence staining was used to assess the aorta and small intestine, and 16S rRNA amplicon sequencing was performed to examine gut bacteria. Transcriptome and metabonomic analyses were conducted to determine the intestinal transcriptome and serum metabolome, respectively. Notably, ARB-modified fecal microbiota transplantation (FMT), results in marked decreases in systolic BP levels, collagen deposition and reactive oxygen species accumulation in the vasculature, and alleviated intestinal structure impairments in SHRs. These changes were linked with the reconstruction of the gut microbiota in SHR recipients post-FMT, especially with a decreased abundance of Lactobacillus, Aggregatibacter, and Desulfovibrio. Moreover, ARB-treated microbes contributed to increased intestinal Ciart, Per1, Per2, Per3, and Cipc gene levels and decreased Nfil3 and Arntl expression were detected in response to ARB-treated microbes. More importantly, circulating metabolites were dramatically reduced in ARB-FMT rats, including 6beta-Hydroxytestosterone and Thromboxane B2. In conclusion, ARB-modified gut microbiota exerts protective roles in vascular remodeling and injury, metabolic abnormality and intestinal dysfunctions, suggesting a pivotal role in mitigating hypertension and providing insights into the cross-talk between antihypertensive medicines and the gut microbiome.

Vascular injury is central to the pathogenesis and progression of cardiovascular diseases, however, fostering alternative strategies to alleviate vascular injury remains a persisting challenge. Given the central role of cell-derived nitric oxide (NO) in modulating the endogenous repair of vascular injury, NO-generating proteolipid nanovesicles (PLV-NO) are designed that recapitulate the cell-mimicking functions for vascular repair and replacement. Specifically, the proteolipid nanovesicles (PLV) are versatilely fabricated using membrane proteins derived from different types of cells, followed by the incorporation of NO-generating nanozymes capable of catalyzing endogenous donors to produce NO. Taking two vascular injury models, two types of PLV-NO are tailored to meet the individual requirements of targeted diseases using platelet membrane proteins and endothelial membrane proteins, respectively. The platelet-based PLV-NO (pPLV-NO) demonstrates its efficacy in targeted repair of a vascular endothelium injury model through systemic delivery. On the other hand, the endothelial cell (EC)-based PLV-NO (ePLV-NO) exhibits suppression of thrombosis when modified onto a locally transplanted small-diameter vascular graft (SDVG). The versatile design of PLV-NO may enable a promising therapeutic option for various vascular injury-evoked cardiovascular diseases.

BACKGROUND: Traumatic proximal tibiofibular fracture and dislocation (PTFD) have been rarely studied and are easily missed in clinical practice. PTFD is considered a marker of severely traumatized knees. The purpose of this study was to retrospectively analyze the incidence and impact of PTFD in traumatized knees with vascular injury.
METHODS: Patients with knee trauma and vascular injury were included from January 2022 to October 2023. X-rays and CT scans of included patients were retrospectively analyzed to determine the presence of PTFD. Patients were further divided into PTFD group and non-PTFD group for further comparative analysis.
RESULTS: A total of 27 patients (28 limbs) were included. Incidence of PTFD was 39.3% (11/28) in traumatic knee with vascular injury, including 8 anterolateral dislocations and 3 posteromedial dislocations. PTFD group had significantly more limbs with open injuries compared with non-PTFD group (10/11 VS 7/17, p<0.05). Amputation rate of PTFD group was as high as 40% (4/10), compared to 23.5% (4/17) in non-PTFD group. However, the difference between two groups was not statistically significant (p>0.05).
CONCLUSIONS: PTFD was easily overlooked or missed. In traumatized knees with vascular injury, incidence of PTFD was high. The presence of PTFD might indicate severe knee trauma and the possibility of open injury. Although there was no significant difference compared with non-PTFD group, PTFD group had a relatively high amputation rate of 40%.

OBJECTIVE: In orthopedic trauma, identification of extremity trauma combined with vascular injury is challenging. Missed diagnosis may result in amputation or even death. The purpose of this study was to investigate whether physical examination combined with handheld vascular ultrasound Doppler examination could be an effective method of screening for peripheral vascular injury and to explore the characteristics of vascular injuries in orthopedic trauma patients.
METHODS: Retrospective analysis of patients in the emergency department of orthopedic trauma in our hospital from January 2022 to October 2023. Physical examination combined with handheld vascular ultrasound Doppler examination was used as a screening method for suspected vascular injuries. Patients with suspected vascular injury would undergo further angiography and receive multidisciplinary treatment. Angiography was used as the gold standard for diagnosing vascular injuries. Patient demographics, mechanism of injury, location and type of injury, angiographic results, surgical notes, and early treatment outcome data were recorded.
RESULTS: A total of 55 cases (58 limb injuries) with suspected vascular injury were ultimately included. Angiography revealed that 53 cases (55 limbs, positive rate 94.8%) were considered to have confirmed vascular injuries. Forty-three were male (81.1%) and 10 were female (18.9%), with mean age 44.1 ± 16.6 years. The main mechanism of injury was traffic accident (30, 56.7%). Most common site of vascular injuries was knee joint (30/55, 54.5%), and popliteal artery (23, 47.9%) was the most commonly injured blood vessel. After multidisciplinary collaborative treatment, overall patient mortality was 3.8% (2/53), and limb survival rate among surviving patients was 81.1% (43/53) in our study.
CONCLUSIONS: In orthopedic trauma, \"Hard signs\" and \"soft signs\" combined with handheld vascular ultrasound Doppler examination were effective ways to screen for suspected vascular injuries. Most limbs had associated fractures or dislocations at the site of vascular injury. Collaboration of vascular surgery, microsurgery and orthopedic trauma may help improve patients\' prognosis.

Aims: Asprosin, a newly discovered hormone, is linked to insulin resistance. This study shows the roles of asprosin in vascular smooth muscle cell (VSMC) proliferation, migration, oxidative stress, and neointima formation of vascular injury. Methods: Mouse aortic VSMCs were cultured, and platelet-derived growth factor-BB (PDGF-BB) was used to induce oxidative stress, proliferation, and migration in VSMCs. Vascular injury was induced by repeatedly moving a guidewire in the lumen of the carotid artery in mice. Results: Asprosin overexpression promoted VSMC oxidative stress, proliferation, and migration, which were attenuated by toll-like receptor 4 (TLR4) knockdown, antioxidant (N-Acetylcysteine, NAC), NADPH oxidase 1 (NOX1) inhibitor ML171, or NOX2 inhibitor GSK2795039. Asprosin overexpression increased NOX1/2 expressions, whereas asprosin knockdown increased heme oxygenase-1 (HO-1) and NADPH quinone oxidoreductase-1 (NQO-1) expressions. Asprosin inhibited nuclear factor E2-related factor 2 (Nrf2) nuclear translocation. Nrf2 activator sulforaphane increased HO-1 and NQO-1 expressions and prevented asprosin-induced NOX1/2 upregulation, oxidative stress, proliferation, and migration. Exogenous asprosin protein had similar roles to asprosin overexpression. PDGF-BB increased asprosin expressions. PDGF-BB-induced oxidative stress, proliferation, and migration were enhanced by Nrf2 inhibitor ML385 but attenuated by asprosin knockdown. Vascular injury increased asprosin expression. Local asprosin knockdown in the injured carotid artery promoted HO-1 and NQO-1 expressions but attenuated the NOX1 and NOX2 upregulation, oxidative stress, neointima formation, and vascular remodeling in mice. Innovation and Conclusion: Asprosin promotes oxidative stress, proliferation, and migration of VSMCs via TLR4-Nrf2-mediated redox imbalance. Inhibition of asprosin expression attenuates VSMC proliferation and migration, oxidative stress, and neointima formation in the injured artery. Asprosin might be a promising therapeutic target for vascular injury.

OBJECTIVE: Bone morphogenetic protein-4 (BMP4) has been proved to be an important regulatory factor for the pathological process of atherosclerosis (AS). However, there are few related clinical studies. This study aims to investigate the levels of plasma BMP4 in patients suffering from the arterial occlusive diseases (ACD) characterized by AS, and further to test the relationship between BMP4 and inflammation and vascular injury.
METHODS: A total of 38 ACD patients (the ACD group) and 38 healthy people for the physical examination (the control group) were enrolled. The plasma in each subject from both groups was obtained to test the levels of BMP4, tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), IL-10, and vascular endothelial cadherin (VE-cadherin), and the relationship between BMP4 and the detected indicators above were further analyzed.
RESULTS: Compared with the control group, the patients in the ACD group displayed significant elevations in the neutrophil to lymphocyte ratio [NLR, 1.63 (1.26, 1.91) vs 3.43 (2.16, 6.61)] and platelet to lymphocyte ratio [PLR, 6.37 (5.26, 7.74) vs 15.79 (7.97, 20.53)], while decrease in the lymphocyte to monocyte ratio [LMR, 5.67 (4.41, 7.14) vs 3.43 (2.07, 3.74)] (all P<0.05). Besides, the ACD patients displayed significant elevations in plasma BMP4 [581.26 (389.85, 735.64) pg/mL vs 653.97(510.95, 890.43) pg/mL], TNF-α [254.16 (182.96, 340.70) pg/mL vs 293.29(238.90, 383.44) pg/mL], and VE-cadherin [1.54 (1.08, 2.13) ng/mL vs 1.85 (1.30, 2.54) ng/mL], and decrease in IL-10 [175.89 (118.39, 219.25) pg/mL vs 135.92 (95.80, 178.04) pg/mL] (all P<0.05). While the levels of IL-1β remained statistically comparable between the 2 groups (P=0.09). Furthermore, the plasma BMP4 levels were further revealed to be positively correlated with the levels of IL-1β (r=0.35), TNF-α (r=0.31) and VE-cadherin (r=0.47), while they were negatively correlated with the levels of IL-10 (r=-0.37; all P<0.01).
CONCLUSIONS: After ACD occurrence, the patients\' plasma concentrations of BMP4 would be upregulated, which may serve as a candidate to indicate the levels of inflammation and vascular injury.
目的: 骨形态发生蛋白-4(bone morphogenentic protein-4，BMP4)在动脉粥样硬化(atherosclerosis，AS)的病理过程中具有重要调节作用，但相关的临床研究较少。本研究拟观察以AS为主要病理特点的动脉阻塞性疾病(arterial occlusive disease，ACD)患者血浆BMP4的表达情况，并分析血浆中BMP4与炎症因子和血管损伤标志物之间的相关性。方法: 共招募38名诊断为ACD的患者(ACD组)和38名体检志愿者(对照组)，抽取ACD组患者术前和对照组体检时的静脉血，比较2组血常规指标的差异。采用酶联免疫吸附试验(enzyme linked immunosorbent assay，ELISA)检测血浆中BMP4、肿瘤坏死因子α(tumor necrosis factor-α，TNF-α)、白细胞介素(interleukin，IL)-1β、IL-10及血管内皮钙黏蛋白(vascular endothelial cadherin，VE-cadherin)的表达变化，并进一步分析BMP4与以上各指标之间的相关性。结果: 与对照组相比，ACD组患者血常规结果表现为中性粒细胞-淋巴细胞比值[neutrophil to lymphocyte ratio，NLR；1.63 (1.26，1.91) vs 3.43(2.16，6.61)]和血小板-淋巴细胞比值[platelet to lymphocyte ratio，PLR；6.37(5.26，7.74) vs 15.79(7.97，20.53)]升高、淋巴细胞-单核细胞比值[lymphocyte to monocyte ratio，LMR；5.67(4.41，7.14) vs 3.43(2.07，3.74)]下降(均P<0.05)；ACD组患者血浆BMP4[581.26(389.85，735.64) pg/mL vs 653.97(510.95，890.43) pg/mL]、TNF-α[254.16(182.96，340.70) pg/mL vs 293.29(238.90，383.44) pg/mL]及内皮标志物VE-cadherin[1.54 (1.08，2.13) ng/mL vs 1.85 (1.30，2.54) ng/mL]的水平均显著升高，而抗炎因子IL-10的水平显著下降[175.89 (118.39，219.25) pg/mL vs 135.92(95.80，178.04) pg/mL](均P<0.05)。2组间促炎因子IL-1β的差异无统计学意义[300.39(205.39，403.56) pg/mL vs 378.46 (243.20，448.69) pg/mL；P=0.09]。相关分析结果表明：血浆BMP4水平与促炎因子IL-1β(r=0.35)、TNF-α(r=0.31)以及内皮标志物VE-cadherin(r=0.47)呈正相关，与抗炎因子IL-10呈负相关(r=-0.37；均P<0.01)。结论: ACD患者血浆BMP4的水平升高，且与患者的炎症水平和血管损伤程度具有相关性。.

The RNA-binding zinc finger protein 36 (ZFP36) family participates in numerous physiological processes including transition and differentiation through post-transcriptional regulation. ZFP36L1 is a member of the ZFP36 family. This study aimed to evaluate the role of ZFP36L1 in restenosis. We found that the expression of ZFP36L1 was inhibited in VSMC-phenotypic transformation induced by TGF-β, PDGF-BB, and FBS and also in the rat carotid injury model. In addition, we found that the overexpression of ZFP36L1 inhibited the proliferation and migration of VSMCs and promoted the expression of VSMC contractile genes; whereas ZFP36L1 interference promoted the proliferation and migration of VSMCs and suppressed the expression of contractile genes. Furthermore, the RNA binding protein immunoprecipitation and double luciferase reporter gene experiments shows that ZFP36L1 regulates the phenotypic transformation of VSMCs through the posttranscriptional regulation of KLF16. Finally, our research results in the rat carotid balloon injury animal model further confirmed that ZFP36L1 regulates the phenotypic transformation of VSMCs through the posttranscriptional regulation of KLF16 and further plays a role in vascular injury and restenosis in vivo.

OBJECTIVE: To explore the effect mechanism of moxibustion with wheat-grain size cone at \"Zusanli\" (ST 36) on vascular injury and oxidative stress in hyperlipidemia through mammalian target of rapamycin (mTOR)/hypoxia inducible factor-1α (HIF-1α)/vascular endothelial growth factor (VEGF) signaling pathway.
METHODS: Forty healthy male SD rats with SPF grade were randomly divided into a normal group, a model group, a moxibustion group, and an inhibitor group, with 10 rats in each one. The hyperlipidemia model was established by feeding a high-fat diet for 8 weeks in rats of the model group, the moxibustion group and the inhibitor group. The moxibustion with wheat-grain size cone was delivered at bilateral \"Zusanli\" (ST 36) of each rat in the moxibustion group and the inhibitor group, with 3 cones on each acupoint in each intervention, once daily for 4 weeks. In the inhibitor group, before each intervention with moxibustion, rapamycin solution was injected intraperitoneally, 2.0 mg/kg. After modeling and intervention, using ELISA, the levels of total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) in the serum of rats were determined. After intervention, with HE staining and oil red O staining adopted, the abdominal aortic morphology and peripheral lipid deposition were observed. Separately, using WST-1, TBA and micro-plate method, the superoxide dismutase (SOD) activity and the levels of malondialdehyde (MDA) and nitric oxide (NO) in the serum were detected. The protein expression of mTOR, HIF-1α and VEGF in abdominal aorta were measured by Western blot method.
RESULTS: Compared with those in the normal group, the levels of TC, TG and LDL-C increased (P<0.01) and HDL-C decreased (P<0.01) in the serum of the rats in the model group, the moxibustion group and the inhibitor group after model establishment. When compared with the normal group after intervention, in the model group, the serum levels of TC, TG, LDL-C and MDA increased (P<0.01), HDL-C level, SOD activity and NO level were reduced (P<0.01); the cell structure of the abdominal arota was abnormal, the peripheral lipids deposited seriously; and the protein expression of mTOR, HIF-1α and VEGF of abdominal aorta was elevated (P<0.01, P<0.05). In comparison with the model group, the levels of TC, TG, LDL-C and MDA were reduced (P<0.01), HDL-C levels, SOD activities and NO levels elevated (P<0.01, P<0.05), as well as the protein expression of mTOR, HIF-1α and VEGF of abdominal aorta (P<0.01, P<0.05) in the moxibustion group and the inhibitor group; besides, the vascular structure was ameliorated and the lipid deposition reduced in the moxibustion group, while, the vascular structure was still abnormal and the lipid deposition declined in the inhibitor group. When compared with the inhibitor group, the serum SOD activity and NO level increased (P<0.05) and MDA decreased (P<0.05); and the protein expression of mTOR, HIF-1α and VEGF of abdominal aorta was elevated (P<0.01, P<0.05) in the moxibustion group.
CONCLUSIONS: The vascular injury due to hyperlipidemia is repaired by moxibustion with wheat-grain size cone at \"Zusanli\" (ST 36) through ameliorating oxidative stress, which is associated potentially with the modulation of mTOR/HIF-1α/VEGF signaling pathway.
目的: 基于哺乳动物雷帕霉素靶蛋白（mTOR）/缺氧诱导因子-1α（HIF-1α）/血管内皮生长因子（VEGF）信号通路探讨麦粒灸“足三里”改善高脂血症血管损伤及氧化应激的效应机制。方法: 将40只健康SPF级雄性SD大鼠随机分为正常组、模型组、艾灸组和抑制剂组，每组10只。模型组、艾灸组、抑制剂组大鼠采用高脂饲料喂养8周建立高脂血症模型。艾灸组与抑制剂组于双侧“足三里”行麦粒灸干预，每次每穴灸3壮，每日1次，共4周。抑制剂组在每次麦粒灸干预前腹腔注射雷帕霉素溶液（2.0 mg/kg）。分别于造模后及干预后采用ELISA法检测大鼠血清总胆固醇（TC）、三酰甘油（TG）、高密度脂蛋白胆固醇（HDL-C）和低密度脂蛋白胆固醇（LDL-C）含量。于干预后采用HE染色、油红O染色观察大鼠腹主动脉形态及周围脂质沉积；分别采用WST-1、TBA和微板法检测血清超氧化物歧化酶（SOD）活性及丙二醛（MDA）、一氧化氮（NO）含量；Western blot法检测大鼠腹主动脉mTOR、HIF-1α、VEGF蛋白表达。结果: 造模后，与正常组比较，模型组、艾灸组、抑制剂组大鼠血清TC、TG、LDL-C含量升高（P<0.01），HDL-C含量降低（P<0.01）。干预后，与正常组比较，模型组大鼠血清TC、TG、LDL-C、MDA含量升高（P<0.01），HDL-C含量、SOD活性及NO含量降低（P<0.01）；腹主动脉组织细胞结构异常、周围脂质沉积较多；腹主动脉mTOR、HIF-1α、VEGF蛋白表达升高（P<0.01，P<0.05）。与模型组比较，艾灸组和抑制剂组大鼠血清TC、TG、LDL-C、MDA含量降低（P<0.01），HDL-C含量、SOD活性及NO含量升高（P<0.01，P<0.05）；腹主动脉mTOR、HIF-1α、VEGF蛋白表达升高（P<0.01，P<0.05）；艾灸组血管组织结构改善、脂质沉积减少，抑制剂组血管组织结构异常、脂质沉积减少。与抑制剂组比较，艾灸组大鼠血清SOD活性、NO含量升高（P<0.05），MDA含量降低（P<0.05）；腹主动脉mTOR、HIF-1α、VEGF蛋白表达升高（P<0.01，P<0.05）。结论: 麦粒灸“足三里”可通过改善氧化应激进而修复高脂饮食导致的血管损伤，其机制与调控mTOR/HIF-1α/VEGF信号通路有关。.

Chronic renal failure (CRF) resulting in vascular calcification, which does damage to blood vessels and endothelium, is an independent risk factor for stroke. It has been reported that cilostazol has a protective effect on the focal cerebral ischemic infarct. However, its impact on vascular injury in CRF combined stroke and its molecular protection mechanism have not been investigated. In this study, we carried out the effect of cilostazol on CRF combined stroke rats, and the results confirmed that it improved the neurobehavior, renal function as well as pathologic changes in both the kidney and brain. In addition, the inflammation and oxidative stress factors in the kidney and brain were suppressed. Moreover, the rates of brain edema and infarction were decreased. The injured brain-blood barrier (BBB) was recovered with less Evans blue extravasation and more expressions of zonula occludens-1(ZO-1) and occludin. More cerebral blood flow (CBF) in the ipsilateral hemisphere and more expression of CD31 and vascular endothelial growth factor (VEGF) in brain and kidney were found in the cilostazol group. Furthermore, cell apoptosis and cell autophagy became less, on the contrary, proteins of vascular endothelial growth factor receptor 2 (VEGFR2) after the cilostazol treatment were increased. More importantly, this protective effect is related to the pathway of Janus Kinase (JAK)/signal transducer and activator of transcription 3 (STAT3), mammalian target of rapamycin (mTOR), and the hypoxia inducible factor-1α (HIF-1α). In conclusion, our results confirmed that cilostazol exerted a protective effect on the brain and kidney function, specifically in vascular injury, oxidative stress, cell apoptosis, cell autophagy, and inflammation response in CRF combined with stroke rats which were related to the upregulation of JAK/STAT3/mTOR signal pathway.
UNASSIGNED: The online version contains supplementary material available at 10.1007/s43188-023-00217-w.