CircZXDC Promotes Vascular Smooth Muscle Cell Transdifferentiation via Regulating miRNA-125a-3p/ABCC6 in Moyamoya Disease

Moyamoya disease (MMD) is an occlusive, chronic cerebrovascular disease affected by genetic mutation and the immune response. Furthermore, vascular smooth muscle cells (VSMCs) and endothelial cells (ECs) participate in the neointima of MMD, but the etiology and pathophysiological changes in MMD vessels remain largely unknown. Therefore, we established the circZXDC (ZXD family zinc finger C)–miR-125a-3p–ABCC6 (ATP-binding cassette subfamily C member 6) axis from public datasets and online tools based on “sponge-like” interaction mechanisms to investigate its possible role in VSMCs. The results from a series of in vitro experiments, such as dual luciferase reporter assays, cell transfection, CCK-8 assays, Transwell assays, and Western blotting, indicate a higher level of circZXDC in the MMD plasma, especially in those MMD patients with the RNF213 mutation. Moreover, circZXDC overexpression results in a VSMC phenotype switching toward a synthetic status, with increased proliferation and migration activity. CircZXDC sponges miR-125a-3p to increase ABCC6 expression, which induces ERS (endoplasmic reticulum stress), and subsequently regulates VSMC transdifferentiation from the contractive phenotype to the synthetic phenotype, contributing to the intima thickness of MMD vessels. Our findings provide insight into the pathophysiological mechanisms of MMD and indicate that the circZXDC–miR-125a-3p–ABCC6 axis plays a pivotal role in the progression of MMD. Furthermore, circZXDC might be a diagnostic biomarker and an ABCC6-specific inhibitor and has the potential to become a promising therapeutic option for MMD

Risk Factors of Transient Neurological Deficits and Perioperative Stroke after Revascularization in Patients with Moyamoya Disease

Objective: To analyze the risk factors of transient neurological deficits (TND) and perioperative stroke in patients with MMD after extracranial–intracranial revascularization. Methods: A retrospective analysis of the clinical data of 183 patients with MMD undergoing 203 EC–IC bypass operation procedures from January 2018 to August 2020. According to whether TND and stroke occurred within 14 days after operation, univariate analysis and multivariate logistic regression were used. Results: TND occurred in 26 cases (12.8%) of revascularization. The results of the univariate analysis showed that history of diabetes, multiple episodes of preoperative symptoms, lesions involving the posterior circulation, and high postoperative blood pressure are the risk factors of TND. Further multivariate logistic regression analysis showed that multiple episodes of preoperative symptoms (p = 0.016) and lesions involving the posterior circulation (p = 0.014) are the independent risk factors for TND. Perioperative stroke occurred in 12 cases (5.9%). The results of the univariate analysis showed that older age, history of hypertension, preoperative cerebral infarction as the main symptom, lesions involving the posterior circulation, and high perioperative blood pressure are the risk factors of perioperative stroke. The results of multivariate logistic regression analysis showed that preoperative cerebral infarction as the main symptom (p = 0.015) is an independent risk factor for perioperative stroke. The occurrence of perioperative complications was not related to the improvement of follow-up mRS (Modified Rankin Scale) score and long-term cerebral rehemorrhage. Conclusions: Clinically, patients with MMD have multiple episodes of preoperative symptoms, lesions involving the posterior circulation, and preoperative cerebral infarction and should be attached when undergoing revascularization

Local transplantation of mesenchymal stem cells improves encephalo-myo-synangiosis-mediated collateral neovascularization in chronic brain ischemia

Abstract Background To explore whether local transplantation of mesenchymal stem cells (MSCs) in temporal muscle can promote collateral angiogenesis and to analyze its main mechanisms of promoting angiogenesis. Methods Bilateral carotid artery stenosis (BCAS) treated mice were administrated with encephalo-myo-synangiosis (EMS), and bone marrow mesenchymal stem cells (BMSCs) were transplanted into the temporal muscle near the cerebral cortex. On the 30th day after EMS, the Morris water maze, immunofluorescence, laser speckle imaging, and light sheet microscopy were performed to evaluate angiogenesis; In addition, rats with bilateral common carotid artery occlusion were also followed by EMS surgery, and BMSCs from GFP reporter rats were transplanted into the temporal muscle to observe the survival time of BMSCs. Then, the concentrated BMSC-derived conditioned medium (BMSC-CM) was used to stimulate HUVECs and BMECs for ki-67 immunocytochemistry, CCK-8, transwell and chick chorioallantoic membrane assays. Finally, the cortical tissue near the temporal muscle was extracted after EMS, and proteome profiler (angiogenesis array) as well as RT-qPCR of mRNA or miRNA was performed. Results The results of the Morris water maze 30 days after BMSC transplantation in BCAS mice during the EMS operation, showed that the cognitive impairment in the BCAS + EMS + BMSC group was alleviated (P < 0.05). The results of immunofluorescence, laser speckle imaging, and light sheet microscopy showed that the number of blood vessels, blood flow and astrocytes increased in the BCAS + EMS + BMSC group (P < 0.05). The BMSCs of GFP reporter rats were applied to EMS and showed that the transplanted BMSCs could survive for up to 14 days. Then, the results of ki-67 immunocytochemistry, CCK-8 and transwell assays showed that the concentrated BMSC-CM could promote the proliferation and migration of HUVECs and BMECs (P < 0.05). Finally, the results of proteome profiler (angiogenesis array) in the cerebral cortex showed that the several pro-angiogenesis factors (such as MMP-3, MMP-9, IGFBP-2 or IGFBP-3) were notably highly expressed in MSC transplantation group compared to others. Conclusions Local MSCs transplantation together with EMS surgery can promote angiogenesis and cognitive behavior in chronic brain ischemia mice. Our study illustrated that MSC local transplantation can be the potential therapeutical option for improving EMS treatment efficiency which might be translated into clinical application