Using 99mTc-(V)-DMSA to follow the vascular calcification process in vascular smooth muscle cells based on pit-1 expression.

BACKGROUND: Vascular calcification is an established feature of atherosclerosis process. The sodium/phosphate transporter PiT-1 acts as a biosensor in vascular calcification of VSMCs. [99mTc]-Pentavalent dimercaptosuccinic acid (99mTc-(V)-DMSA) was mediated by PiT-1 transporter in tumoral cells and we propose its evaluation in a vascular calcification in vitro model. The aim of this study was to determine if 99mTc-(V)-DMSA can follow the vascular calcification process in vascular smooth muscle cells (VSMCs) based on PiT-1 expression. METHODS: From a rat aortic VSMC cell line (A7r5), we set up a model of calcification within 7 days using a calcifying medium containing a high inorganic phosphate concentration. Phosphocalcic deposits were monitored with Alizarin red and Von Kossa staining and with phase contrast microscopy. PiT-1 expression was evaluated with an immunofluorescence assay and osteopontin expression, with whole cell ELISA assay. 99mTc-(V)-DMSA uptake was measured in control and calcifying conditions and compared with optical microscopy evaluation. RESULTS: Under hyperphosphatemia conditions, the VSMC cells progressively overexpressed osteopontin protein, PiT-1 transporter, and synthetized mineralized matrix with phosphocalcic deposition. 99mTc-(V)-DMSA uptake was to 2.8±2.08%DA/mg-protein in control cells and 42±24%DA/mg-protein in calcified cells (P<0.001). PiT-1 inhibition with phosphonoformic acid completely reverse the calcium deposition as well as the 99mTc-(V)-DMSA uptake. These results demonstrated that 99mTc-(V)-DMSA in-vitro uptake is mediated by PiT-1 transporter and follow the VSMC calcification process. CONCLUSIONS: These preliminary in-vitro results showed 99mTc-(V)-DMSA uptake follow the phospho-calcic deposition mediated by PiT-1 transporter. This radiotracer may have some potential to detect changes of VSMC metabolism occurring in the atherosclerosis process.

Distinct signatures of calcium activity in brain mural cells.

Pericytes have been implicated in various neuropathologies, yet little is known about their function and signaling pathways in health. Here, we characterized calcium dynamics of cortical mural cells in anesthetized or awake Pdgfrb-CreERT2;Rosa26< LSL-GCaMP6s > mice and in acute brain slices. Smooth muscle cells (SMCs) and ensheathing pericytes (EPs), also named as terminal vascular SMCs, revealed similar calcium dynamics in vivo. In contrast, calcium signals in capillary pericytes (CPs) were irregular, higher in frequency, and occurred in cellular microdomains. In the absence of the vessel constricting agent U46619 in acute slices, SMCs and EPs revealed only sparse calcium signals, whereas CPs retained their spontaneous calcium activity. Interestingly, chemogenetic activation of neurons in vivo and acute elevations of extracellular potassium in brain slices strongly decreased calcium activity in CPs. We propose that neuronal activation and an extracellular increase in potassium suppress calcium activity in CPs, likely mediated by Kir2.2 and KATP channels.

Variants of Focal Adhesion Scaffold Genes Cause Thoracic Aortic Aneurysm.

RATIONALE: Thoracic aortic aneurysm (TAA) leads to substantial mortality worldwide. Familial and syndromic TAAs are highly correlated with genetics. However, the incidence of sporadic isolated TAA (iTAA) is much higher, and the genetic contribution is not yet clear. OBJECTIVE: Here, we examined the genetic characteristics of sporadic iTAA. METHODS AND RESULTS: We performed a genetic screen of 551 sporadic iTAA cases and 1071 controls via whole-exome sequencing. The prevalence of pathogenic mutations in known causal genes was 5.08% in the iTAA cohort. We selected 100 novel candidate genes using a strict strategy, and the suspected functional variants of these genes were significantly enriched in cases compared with controls and carried by 60.43% of patients. We found more severe phenotypes and a lower proportion of hypertension in cases with pathogenic mutations or suspected functional variants. Among the candidate genes, Testin (TES), which encodes a focal adhesion scaffold protein, was identified as a potential TAA causal gene, accounting for 4 patients with 2 missense variants in the LIM1 domain (c.751T>C encoding p.Y251H; c.838T>C encoding p.Y280H) and highly expressed in the aorta. The 2 variants led to a decrease in TES expression. The thoracic aorta was spontaneously dilated in the TesY249H knock-in and Tes-/- mice. Mechanistically, the p.Y249H variant or knockdown of TES led to the repression of vascular smooth muscle cell contraction genes and disturbed the vascular smooth muscle cell contractile phenotype. Interestingly, suspected functional variants of other focal adhesion scaffold genes, including TLN1 (Talin-1) and ZYX (zyxin), were also significantly enriched in patients with iTAA; moreover, their knockdown resulted in decreased contractility of vascular smooth muscle cells. CONCLUSIONS: For the first time, this study revealed the genetic landscape across iTAA and showed that the focal adhesion scaffold genes are critical in the pathogenesis of iTAA.

Bifunctional supramolecular nanofiber inhibits atherosclerosis by enhancing plaque stability and anti-inflammation in apoE-/- mice.

Background and Purpose: Atherosclerosis is vascular disease of chronic inflammation and lipid disorder, which is a major cause of coronary heart disease. Foam cell formation is key progress during the atherosclerosis development. Insulin-like growth factor (IGF)-1 is a growth hormone that plays a crucial role in growth, metabolism, and homeostasis. Previous studies have demonstrated that increase in circulating IGF-1 can reduce atherosclerotic burden. However, active IGF-1 is characterized with poor tissue retention and is at a very low level in circulation system. Therefore, supplementation of exogenous IGF-1 to restore the physiological level is a promising approach to inhibit atherosclerosis. In this study, we develop a self-assembling, anti-inflammatory drug-modified peptide derived from IGF-1 to mimic IGF-1 bioactivity and simultaneously with an anti-inflammatory property for the treatment of atherosclerosis. Methods: ApoE-/- mice were subcutaneously (s.c.) injected with the different hydrogels or natural IGF-1 protein solution per week and simultaneously fed a high-fat diet for 16 weeks. Atherosclerotic lesion formation and stability were assessed after treatment. Moreover, peritoneal macrophage and serum samples were collected to determine lipid profile and inflammatory cytokines. Concurrently, we determined the effect of bifunctional supramolecular nanofibers/hydrogel on cholesterol efflux, foam cell formation, phenotypic transformation of VSMC to macrophage-like cells, and macrophage polarization in vitro or in vivo. Results: Bifunctional supramolecular nanofibers/hydrogel for the treatment of atherosclerosis was formed by a short peptide consisting of a tetrapeptide SSSR from C-region of growth factor IGF-1, an anti-inflammatory drug naproxen (Npx), and a powerful self-assembling D-peptide DFDF. The resulting hydrogel of Npx-DFDFGSSSR (Hydrogel 1, H1) possessed both the anti-inflammatory and IGF-1 mimicking properties, and it efficiently promoted the expression of ABCA1 and ABCG1, thereby significantly reducing cholesterol accumulation in macrophages and preventing foam cell formation. Moreover, H1 markedly inhibited the transformation of vascular smooth muscle cells (VSMCs) into macrophage-like cells which also contributed to foam cell formation. In addition, H1 significantly reduced the inflammatory response in vitro and in vivo. Most importantly, the IGF-1 mimetic peptide showed comparable performance to IGF-1 in vivo and inhibited atherosclerosis by markedly reducing lesion area and enhancing plaque stability. Conclusions: Our study provides a novel supramolecular nanomaterial to inhibit pathological progress of atherosclerosis through regulating cholesterol efflux and inflammation, which may contribute to the development of a promising nanomedicine for the treatment of atherosclerosis in the clinic.

High-resolution iris and retinal imaging in multisystemic smooth muscle dysfunction syndrome due to a novel Asn117Lys substitution in ACTA2: a case report.

BACKGROUND: Congenital mydriasis and retinal arteriolar tortuosity are associated with the life-threatening multisystemic smooth muscle dysfunction syndrome (MSMDS) due to mutations in the gene, ACTA2, which encodes alpha-smooth muscle actin (α-SMA). Previous reports attributed MSMDS-related congenital mydriasis to the absence of iris sphincter muscle. Similarly, it has been hypothesized that abnormal proliferation of the vascular smooth muscle cells causes the marked tortuosity of retinal arterioles in MSMDS. In this report, high-resolution ocular imaging reveals unexpected findings that reject previous hypotheses. CASE PRESENTATION: The proband is a 37-year-old female with a history of neonatal patent ductus arteriosus (PDA) ligation, left-sided choreiform movements at the age of 11 and a transient aphasia with right-sided weakness at the age of 30. Her older sister also had PDA ligation and congenital mydriasis but no neurological deficit up to age 41. Magnetic resonance angiogram demonstrated cerebrovascular lesions resembling but distinct from Moyamoya disease, characterised by internal carotid artery dilatation, terminal segment stenosis and absent basal collaterals. Their mother had poorly reactive pupils with asymptomatic cerebral arteriopathy resembling her daughters. All three had prominent retinal arteriolar tortuosity. The daughters were heterozygous and the mother was a somatic mosaic for a novel c.351C > G (p.Asn117Lys) transversion in ACTA2. Iris optical coherence tomography (OCT) showed a hyporeflective band anterior to the pigment epithelium indicating the presence of dysfunctional sphincter muscle. Adaptive optics retinal imaging showed no thickening of the arteriolar vessel wall whilst OCT angiography showed extreme corkscrew course of arterioles suggesting vessel elongation. CONCLUSIONS: In addition to the known association between Met46, Arg179 and Arg258 substitutions and ACTA2-related arteriopathy, this case illustrates the possibility that Asn117 also plays an important role in α-SMA function within the cerebrovascular smooth muscle cell. MSMDS-related congenital mydriasis is due to reduced iris sphincter contractility rather than its absence. Retinal arteriolar tortuosity might be due to longitudinal proliferation of arteriolar smooth muscle cells. The described cerebrovascular and ocular signs are consistent with predicted effects of the novel Asn117Lys substitution in ACTA2.

Diagnostic Criteria of Flow-Mediated Vasodilation for Normal Endothelial Function and Nitroglycerin-Induced Vasodilation for Normal Vascular Smooth Muscle Function of the Brachial Artery.

Background Diagnostic criteria of flow-mediated vasodilation (FMD), an index of endothelial function, and nitroglycerin-induced vasodilation (NID), an index of vascular smooth muscle function, of the brachial artery have not been established. The purpose of this study was to propose diagnostic criteria of FMD and NID for normal endothelial function and normal vascular smooth muscle function. Methods and Results We investigated the cutoff values of FMD and NID in subjects with (risk group) and those without cardiovascular risk factors or cardiovascular diseases (no-risk group) in 7277 Japanese subjects (mean age 51.4±10.8 years) from the Flow-Mediated Dilation Japan study and the Flow-Mediated Dilatation Japan Registry study for analysis of the cutoff value of FMD and in 1764 Japanese subjects (62.2±16.1 years) from the registry of Hiroshima University Hospital for analysis of the cutoff value of NID. Receiver-operator characteristic curve analysis of FMD to discriminate subjects in the no-risk group from patients in the risk group showed that the optimal cutoff value of FMD to diagnose subjects in the no-risk group was 7.1%. Receiver-operator characteristic curve analysis of NID to discriminate subjects in the no-risk group from patients in the risk group showed that the optimal cutoff value of NID to diagnose subjects in the no-risk group was 15.6%. Conclusions We propose that the cutoff value for normal endothelial function assessed by FMD of the brachial artery is 7.1% and that the cutoff value for normal vascular smooth muscle function assessed by NID of the brachial artery is 15.6% in Japanese subjects. Clinical Trial Registration www.umin.ac.jp Unique identifiers: UMIN000012950, UMIN000012951, UMIN000012952, and UMIN000003409.

Precapillary sphincters maintain perfusion in the cerebral cortex.

Active nerve cells release vasodilators that increase their energy supply by dilating local blood vessels, a mechanism termed neurovascular coupling and the basis of BOLD functional neuroimaging signals. Here, we reveal a mechanism for cerebral blood flow control, a precapillary sphincter at the transition between the penetrating arteriole and first order capillary, linking blood flow in capillaries to the arteriolar inflow. The sphincters are encircled by contractile mural cells, which are capable of bidirectional control of the length and width of the enclosed vessel segment. The hemodynamic consequence is that precapillary sphincters can generate the largest changes in the cerebrovascular flow resistance of all brain vessel segments, thereby controlling capillary flow while protecting the downstream capillary bed and brain tissue from adverse pressure fluctuations. Cortical spreading depolarization constricts sphincters and causes vascular trapping of blood cells. Thus, precapillary sphincters are bottlenecks for brain capillary blood flow.

IN VIVO OBSERVATION OF RETINAL VASCULAR DEPOSITS USING ADAPTIVE OPTICS IMAGING IN FABRY DISEASE.

PURPOSE: To report a novel finding in patients with Fabry disease, that is, the observation by adaptive optics ophthalmoscopy of intracellular lipidic deposits in retinal vessels. METHODS: Observational two-center case series. Eighteen patients with genetically proven Fabry disease underwent flood-illumination adaptive optics ophthalmoscopy imaging (rtx1; Imagine Eyes, Orsay, France) of retinal vessels. RESULTS: Fourteen patients (78% of all patients; 7 of the 10 women and 7 of the 8 men) showed paravascular punctuate or linear opacities in both eyes. In the least-affected patients, these were seen only in the wall of precapillary arterioles as discrete spots of 5 µm to 10 µm large, whereas in those more severely affected, capillaries and first-order vessels were also involved with diffuse opacification of the wall. These deposits sometime showed a striated pattern, suggesting colocalization with vascular smooth muscle cells. CONCLUSION: Adaptive optics ophthalmoscopy of retinal vessels may be of interest for patients with Fabry disease, providing noninvasive, gradable evaluation of microvascular involvement.

Lessons from Vessel Wall Imaging of Intracranial Aneurysms: New Era of Aneurysm Evaluation beyond Morphology.

Recent basic studies have clarified that aneurysmal wall inflammation plays an important role in the pathophysiology of intracranial aneurysms. However, it remains an interdisciplinary challenge to visualize aneurysm wall status in vivo. MR-vessel wall imaging (VWI) is a current topic of advanced imaging techniques since it could provide an additional value for unruptured intracranial aneurysms (UIAs) risk stratification. With regard to ruptured intracranial aneurysms, VWI could identify a ruptured aneurysm in patients with multiple intracranial aneurysms. Intraluminal thrombus could be a clue to interpret aneurysm wall enhancement on VWI in ruptured intracranial aneurysms. The interpretation of VWI findings in UIAs would require much caution. Actually aneurysm wall enhancement in VWI was significantly associated with consensus morphologic risk factors. However, aneurysmal wall with contrast enhancement oftentimes associated with atherosclerotic, degenerated and thickened wall structure. It remains ill defined if thin wall without wall enhancement (oftentimes invisible in VWI) could be actually safe or look over wall vulnerability. We reviewed currently available studies, especially focusing on VWI for intracranial aneurysms and discussed the clinical utility of VWI.

Quantification of spiral artery remodelling using an Adobe Photoshop-based technique.

Uterine spiral arteries undergo remodelling in normal pregnancy, with replacement of the musculoelastic arterial media by fibrinoid containing extravillous trophoblast cells. Deficient spiral artery remodelling is associated with several adverse pregnancy outcomes. Although there are distinct components of spiral artery remodelling, assessment is subjective and often based on an overall impression of morphology. We aimed to develop a quantitative approach for assessment of uterine spiral artery remodelling. Placental bed biopsies were immunostained using smooth muscle markers, digital images of spiral arteries were captured and Adobe Photoshop was used to analyse positive immunostaining. The method was then used to investigate variation in the same vessel at different levels within a paraffin block, and the effect of parity, pre-eclampsia or miscarriage on vascular smooth muscle cell content. Results were also compared with a more subjective morphology-based assessment system. There was good intra- and interobserver agreement and the method correlated well with the more subjective assessment system. There was an overall reduction in vascular smooth muscle, as detected by caldesmon 1 (h-caldesmon) immunopositivity, with increasing gestational age from 8 weeks to term. A previous pregnancy did not affect the amount of spiral artery smooth muscle. Comparison of pre-eclampsia and late miscarriage samples with controls of the appropriate gestational age demonstrated increased medial smooth muscle in pathological samples. This technique provides a simple, rapid, reproducible and inexpensive approach to quantitative assessment of spiral artery remodelling in normal and pathological human pregnancy, a process which although fundamental for successful pregnancy, is still incompletely understood.

Imaging mass spectrometry reveals heterogeneity of proliferation and metabolism in atherosclerosis.

Atherosclerotic plaques feature local proliferation of leukocytes and vascular smooth muscle cells (VSMCs) and changes in cellular metabolism. Yet the relationship between glucose utilization and proliferation has been technically impossible to study directly in cells of atherosclerotic plaques in vivo. We used multi-isotope imaging mass spectrometry (MIMS), a quantitative imaging platform, to measure coincident cell division and glucose utilization at suborganelle resolution in atherosclerotic plaques. In established plaques, 65% of intimal foam cells and only 4% of medial VSMCs were labeled with 15N-thymidine after 1 week of isotope treatment. Dividing cells demonstrated heightened glucose labeling. MIMS detected 2H-glucose label in multiple subcellular compartments within foam cells, including lipid droplets, the cytosol, and chromatin. Unexpectedly, we identified an intensely focal region of 2H-label in VSMCs underlying plaques. This signal diminished in regions of aorta without atherosclerosis. In advanced plaques, 15N-thymidine and 2H-glucose labeling in foam cells and VSMCs significantly decreased. These data demonstrate marked heterogeneity in VSMC glucose metabolism that was dependent on both proliferative status and proximity of VSMCs to plaques. Furthermore, these results reveal how quantitative mass spectrometry coupled with isotope imaging can complement other methods used to study cell biology directly in the growing atherosclerotic plaque in vivo.

Volumetric optoacoustic tomography enables non-invasive in vivo characterization of impaired heart function in hypoxic conditions.

Exposure to chronic hypoxia results in pulmonary hypertension characterized by increased vascular resistance and pulmonary vascular remodeling, changes in functional parameters of the pulmonary vasculature, and right ventricular hypertrophy, which can eventually lead to right heart failure. The underlying mechanisms of hypoxia-induced pulmonary hypertension have still not been fully elucidated while no curative treatment is currently available. Commonly employed pre-clinical analytic methods are largely limited to invasive studies interfering with cardiac tissue or otherwise ex vivo functional studies and histopathology. In this work, we suggest volumetric optoacoustic tomography (VOT) for non-invasive assessment of heart function in response to chronic hypoxia. Mice exposed for 3 consecutive weeks to normoxia or chronic hypoxia were imaged in vivo with heart perfusion tracked by VOT using indocyanide green contrast agent at high temporal (100 Hz) and spatial (200 µm) resolutions in 3D. Unequivocal difference in the pulmonary transit time was revealed between the hypoxic and normoxic conditions concomitant with the presence of pulmonary vascular remodeling within hypoxic models. Furthermore, a beat-to-beat analysis of the volumetric image data enabled identifying and characterizing arrhythmic events in mice exposed to chronic hypoxia. The newly introduced non-invasive methodology for analysis of impaired pulmonary vasculature and heart function under chronic hypoxic exposure provides important inputs into development of early diagnosis and treatment strategies in pulmonary hypertension.

Correlation of computed tomography with carotid plaque transcriptomes associates calcification with lesion-stabilization.

BACKGROUND AND AIMS: Unstable carotid atherosclerosis causes stroke, but methods to identify patients and lesions at risk are lacking. We recently found enrichment of genes associated with calcification in carotid plaques from asymptomatic patients. Here, we hypothesized that calcification represents a stabilising feature of plaques and investigated how macro-calcification, as estimated by computed tomography (CT), correlates with gene expression profiles in lesions. METHODS: Plaque calcification was measured in pre-operative CT angiographies. Plaques were sorted into high- and low-calcified, profiled with microarrays, followed by bioinformatic analyses. Immunohistochemistry and qPCR were performed to evaluate the findings in plaques and arteries with medial calcification from chronic kidney disease patients. RESULTS: Smooth muscle cell (SMC) markers were upregulated in high-calcified plaques and calcified plaques from symptomatic patients, whereas macrophage markers were downregulated. The most enriched processes in high-calcified plaques were related to SMCs and extracellular matrix (ECM) organization, while inflammation, lipid transport and chemokine signaling were repressed. These findings were confirmed in arteries with high medial calcification. Proteoglycan 4 (PRG4) was identified as the most upregulated gene in association with plaque calcification and found in the ECM, SMA+ and CD68+/TRAP + cells. CONCLUSIONS: Macro-calcification in carotid lesions correlated with a transcriptional profile typical for stable plaques, with altered SMC phenotype and ECM composition and repressed inflammation. PRG4, previously not described in atherosclerosis, was enriched in the calcified ECM and localized to activated macrophages and smooth muscle-like cells. This study strengthens the notion that assessment of calcification may aid evaluation of plaque phenotype and stroke risk.

Nicotine-mediated autophagy of vascular smooth muscle cell accelerates atherosclerosis via nAChRs/ROS/NF-κB signaling pathway.

BACKGROUND AND AIMS: Cigarette smoking is an established risk factor for atherosclerosis. Nicotine, the major constituent of cigarettes, mediates the phenotype switching of vascular smooth muscle cells (VSMCs) and contributes to atherogenesis. Recent studies show that autophagy regulates atherogenesis via several pathways. The aim of this study is to determine whether nicotine regulates autophagy and subsequently mediates the phenotypic transition of VSMCs. METHODS AND RESULTS: Oil Red O and HE staining of aortic sections of ApoE-/- mice showed that nicotine promoted atherosclerosis, and in situ expression of α-SMA indicated the involvement of VSMCs. Western blotting documented that nicotine induced the aorta autophagy. Cultured VSMCs treated with nicotine resulted in the increase of LC3 II-to-LC3 I ratio and the decrease of P62, along with GFP-LC3 puncta assay and transmission electron microscopy, further reflecting nicotine-induced autophagy. In addition, Western blotting and quantitative real-time PCR showed that VSMCs exposed to nicotine underwent changes in the expression of differentiation markers (α-SMA, SM22α and osteopontin), confirming the role of nicotine in VSMC differentiation. Transwell migration and scratch assays demonstrated that nicotine increased the migratory capacity of VSMCs. Finally, nicotine also increased the levels of reactive oxygen species (ROS), as measured by DCFH-DA staining. After respectively inhibiting autophagy (3-MA), oxidative stress (NAC), NF-κB activity (BAY 11-7082, si-p65) and nicotinic acetylcholine receptors (nAChRs, hexamethonium), nicotine-induced autophagy and VSMC phenotype switching were reversed. CONCLUSIONS: Nicotine-induced autophagy promotes the phenotype switching of VSMCs and accelerates atherosclerosis, which is partly mediated by the nAChRs/ROS/NF-κB signaling pathway.

Echo-tracking evaluation of changes in common carotid artery wall elasticity after smoking cessation.

The aim of this study was to explore changes in the common carotid arterial wall elasticity after smoking cessation. Carotid artery ultrasonographic examination was performed in 136 patients, then 1 or 2 years after smoking cessation. We used echo-tracking (ET) to measure stiffness index (ß), pressure-strain elasticity modulus (Ep), arterial compliance (AC), augmentation index (AI), and local pulse wave velocity (PWVß). Patients were divided into four groups based on whether or not they successfully stopped smoking (groups M and N, respectively) and whether (groups M2 and N2, respectively) or not (groups M1 and N1, respectively) they showed comorbidities. In group M1, ß, Ep and PWVß were lower at 1 year than before smoking cessation, while AC and AI did not change. At 2 years, ß, Ep, PWVß, and AC, but not AI, improved further. In group M2, ß, Ep, and PWVß decreased at 2 years, whereas AC and AI did not change. In groups N1 and N2, none of the variables changed significantly. ET can be used quantitatively to evaluate the impact of smoking cessation on the elasticity of the common carotid artery wall.

ACTA2 Cerebral Arteriopathy: Not Just a Puff of Smoke.

BACKGROUND: Missense mutations in the gene that codes for smooth muscle actin, ACTA2, cause diffuse smooth muscle dysfunction and a distinct cerebral arteriopathy collectively known as multisystemic smooth muscle dysfunction syndrome (MSMDS). Until recently, ACTA2 cerebral arteriopathy was considered to be a variant of moyamoya disease. However, recent basic science and clinical data have demonstrated that the cerebral arteriopathy caused by mutant ACTA2 exhibits genetic loci, histopathology, neurological sequelae, and radiographic findings unique from moyamoya disease. We conducted a literature review to provide insight into the history, clinical significance, and neurosurgical management of this recently described novel cerebral arteriopathy. SUMMARY: We performed a literature search using PubMed with the key words "ACTA2 mutation," "ACTA2 cerebral arteriopathy," and "multisystemic smooth muscle dysfunction syndrome." Case reports with confirmed ACTA2 mutations and cerebral arteriopathy were included in our review. Our literature search revealed 15 articles (58 cases) of confirmed ACTA2 cerebral arteriopathy. Distinctive features of this arteriopathy included an aberrant internal carotid circulation with dilatation of the proximal segments, occlusive disease at the distal segments, and dolichoectasia. As such, mutant ACTA2 predisposed patients to ischemic strokes as children. Direct and indirect cerebral revascularization procedures are the mainstay treatment options with varying degrees of success. Key Messages: ACTA2 cerebral arteriopathy is a recently described novel cerebrovascular disease seen in patients with MSMDS. Patients currently diagnosed with moyamoya disease who also have dysfunction of smooth muscle organs may benefit from reevaluation by a medical geneticist and ACTA2 genotyping.

Vascular wall imaging in reversible cerebral vasoconstriction syndrome - a 3-T contrast-enhanced MRI study.

BACKGROUND: Limited histopathology studies have suggested that reversible cerebral vasoconstriction syndromes (RCVS) does not present with vascular wall inflammation. Previous vascular imaging studies have had inconsistent vascular wall enhancement findings in RCVS patients. The aim of this study was to determine whether absence of arterial wall pathology on imaging is a universal finding in patients with RCVS. METHODS: We recruited patients with RCVS from Taipei Veterans General Hospital prospectively from 2010 to 2012, with follow-up until 2017 (n = 48). We analyzed the characteristics of vascular wall enhancement in these patients without comparisons to a control group. All participants received vascular wall imaging by contrasted T1 fluid-attenuated inversion recovery with a 3-T magnetic resonance machine. The vascular wall enhancement was rated as marked, mild or absent. RESULTS: Of 48 patients with RCVS, 22 (45.8%) had vascular wall enhancement (5 marked and 17 mild). Demographics, clinical profiles, and cerebral artery flow velocities were similar across patients with versus without vascular wall enhancement, except that patients with vascular wall enhancement had fewer headache attacks than those without (p = 0.04). Follow-up imaging completed in 14 patients (median interval, 7 months) showed reduced enhancement in 9 patients, but persistent enhancement in 5. CONCLUSION: Almost half of our RCVS patients exhibited imaging enhancement of diseased vessels, and it was persistent for approximately a third of those patients with follow-up imaging. Both acute and persistent vascular wall enhancement may be unhelpful for differentiating RCVS from central nervous system vasculitis or subclinical atherosclerosis.

Clinical Significance of Circumferential Aneurysmal Wall Enhancement in Symptomatic Patients with Unruptured Intracranial Aneurysms: a High-resolution MRI Study.

BACKGROUND AND PURPOSE: The estimates on the risk of rupture of intracranial aneurysms remain a controversial topic. Circumferential aneurysmal wall enhancement (CAWE) on vessel wall magnetic resonance imaging (MRI) has been described in unstable aneurysms. Sentinel headaches and third nerve palsy are possible symptoms prior to the rupture of intracranial aneurysms. In this study, we aimed to demonstrate that CAWE could be associated with these symptoms. METHODS: We performed a retrospective analysis of consecutive symptomatic or asymptomatic patients with unruptured intracranial aneurysms who were examined by high-resolution MRI from October 2014 to November 2016. Two experienced neurovascular radiologists read the images independently and determined whether there was CAWE of the unruptured intracranial aneurysms. Then, we compared variable factors between patients with and without symptoms through univariate comparison and multivariable logistic regression analyses. RESULTS: A total of 45 unruptured intracranial aneurysms were detected in 37 patients. The agreement between 2 experienced readers for CAWE was good (kappa = 0.82; 95% confidence interval 0.66-0.99). CAWE of unruptured intracranial aneurysm was more frequently observed in symptomatic than in asymptomatic patients (16/23, 69.6% versus 6/22, 27.3%, respectively, P < 0.05). The CAWE was the only independent factor associated with symptoms in the multivariable logistic regression analysis (odds ratio 5.17; 95% confidence interval 1.30-20.52; P = 0.02). CONCLUSIONS: Our study demonstrates that CAWE correlated with sentinel headaches and third nerve palsy caused by unruptured aneurysms, and this may be an additional clue to distinguish the cause of these symptoms.

Chemical imaging of fresh vascular smooth muscle cell response by epi-detected stimulated Raman scattering.

An understanding of deformation of cardiovascular tissue under hemodynamic load is crucial for understanding the health and disease of blood vessels. In the present work, an epi-detected stimulated Raman scattering (epi-SRS) imaging platform was designed for in situ functional imaging of vascular smooth muscle cells (VMSCs) in fresh coronary arteries. For the first time, the pressure-induced morphological deformation of fresh VSMCs was imaged with no fixation and in a label-free manner. The relation between the loading pressure and the morphological parameters, including angle and length of the VSMCs, were apparent. The morphological responses of VMSCs to drug treatment were also explored, to demonstrate the capability of functional imaging for VSMCs by this method. The time-course imaging revealed the drug induced change in angle and length of VSMCs. The present study provides a better understanding of the biomechanical framework of blood vessels, as well as their responses to external stimulations, which are fundamental for developing new strategies for cardiovascular disease treatment.

Effect of Simvastatin on Proliferation of Vascular Smooth Muscle Cells During Delayed Cerebral Vasospasm After Subarachnoid Hemorrhage.

AIM: To explore the effect of simvastatin on proliferation of vascular smooth muscle cells (VSMCs) during delayed cerebral vasospasm (dCVS) after subarachnoid hemorrhage (SAH). MATERIAL AND METHODS: Thirty-six male New Zealand White rabbits were randomly divided into three groups: 1) Control group (n=12): given conventional breeding and normal sodium (0.9%) was injected twice into the cisterna magna. 2) SAH group (n=12): given conventional breeding and a SAH model was established. 3) Simvastatin + SAH group (n=12): given conventional breeding and simvastatin for one week, and then a SAH model was established. The first cerebral angiography was conducted before the first injection of sodium or autologous blood into the cisterna magna. The second angiography was done three days after the second injection. The ultrastructural pathology of the basilar artery was compared in three groups. The expression of platelet-derived growth factor-ß (PDGF-ß), proliferating cell nuclear antigen (PCNA) and α-smooth muscle actin (α-SMA) in VSMCs was analysed by RT-PCR. RESULTS: Angiography examinations showed that the basilar artery was obviously contracted in the SAH group and dCVS was confirmed existence after blood injection into the cisterna magna twice. The thickness of VSMCs in the SAH group increased and the expression of PDGF-ß, PCNA, and α-SMA in SAH group were all increased compared to the control group (p < 0.05), and decreased while prophylactic giving simvastatin (p < 0.05). CONCLUSION: Simvastatin may relieve dCVS after SAH by inhibiting the proliferation of VSMCs.