Imaging spectrum of extracranial arterial vascular pathology: pearls for the radiologist.

Non-invasive imaging plays an increasingly important role in assessing the extracranial vasculature. The applications of computed tomography angiography (CTA) and magnetic resonance angiography (MRA) continue to expand with growing demand for stroke imaging and anatomical assessment preceding vascular intervention. Imaging of the neck is performed for a variety of clinical indications with different imaging protocols. Even on non-dedicated vascular imaging, such as soft-tissue studies, the neck vessels and the proximal aortic arch are readily evaluable, providing an opportunity to promptly identify critical vascular abnormalities with significant therapeutic implications. Vascular abnormalities can have non-specific clinical signs and symptoms resulting in delays in both diagnosis and treatment. Understanding the common locations and appearances of vascular pathologies will help the radiologist to develop a systematic search strategy for evaluating neck imaging. Not only is identifying the pathology of paramount importance but also understanding how imaging further prognosticates and determines treatment options. As imaging techniques advance, further vascular radiological features are recognised with therapeutic implications, particularly for stroke. Such features include plaque morphology and vulnerability with imaging helping to identify those at high risk of stroke and recurrent strokes. Using clinical cases from a quaternary care academic medical centre a spectrum of clinically relevant arterial pathologies and associated features that could add further benefit to the radiology report are illustrated. A suggested systematic approach to evaluating the vasculature on neck imaging is also presented.

Learning from mistakes when reporting urgent and emergency vascular studies.

The majority of out-of-hours cases relate to neurological, chest, and gastrointestinal pathologies with acute vascular cases being encountered less commonly. Trainees and exposure of non-vascular/interventional radiology (IR) consultants to angiographic imaging is often limited in working hours and this may lead to reporting on-call cases outside of normal daytime practice. In a recent local review, a number on-call vascular studies were found to contain a number of vascular-related discrepancies. Vascular reporting is a complex subspecialty, which comprises many clear diagnoses (large vessel occlusions, large vessel aneurysms, or dissections); however, also several subtle and complex abnormalities. These more subtle abnormalities, at times, require dedicated vascular specialist review to ensure subtle findings are communicated appropriately to the clinical team. The recent increased complexity of endovascular treatments and their complications has also provided further challenge for the non-specialist reporter. Similarly, improved imaging techniques have allowed for non-obvious but significant findings that may require urgent management, such as small aneurysms and dissection flaps. We will review a range of key vascular findings that demonstrate learning opportunities, particularly within the acute and on-call settings. These will include gastrointestinal haemorrhage, subtle aortic pathologies, head and neck vascular emergencies, small to mid-sized vessel injuries and imaging of post-procedural complications. Educational hints and tips will be provided to enable learning from mistakes encountered by trainees and non-vascular specialist radiologists in the on-call or urgent reporting settings, and these will be reviewed with reference to the literature.

Decreased body-fat accumulation and increased vasorelaxation to glyceryl trinitrate in middle-aged male rats following six-weeks consumption of coconut milk protein

Abstract We investigated whether coconut milk protein (CMP) contributes to the beneficial effects of coconut milk consumption on cardiovascular health markers previously found in middle-aged rats. CMP was isolated and precipitated from dried fresh coconut milk, then gavaged (1 g/kg) to middle-aged male rats for six weeks; control rats received distilled water. Compared to controls, CMP caused decreased body fat and lipid accumulation in liver cells and the platelet count. CMP did not affect basal blood pressure or heart rate in anesthetized rats. Vascular responsiveness to phenylephrine, DL-propargylglycine (PAG), acetylcholine or sodium nitroprusside was unaffected, but vasorelaxation to glyceryl trinitrate (GTN) increased. Effects of ODQ on vasorelaxation to GTN were similar in both groups. Expression of blood vessel eNOS, CSE and sGC was normal. The cyclic guanosine monophosphate (cGMP) level of CMP-treated rats was normal but addition of GTN increased cGMP and NO concentration more in CMP-treated rats than in controls, an effect unaltered by addition of diadzin. Taken together, CMP appears partially responsible for the improvement in cardiovascular health markers caused by coconut milk in middle-aged male rats

Hexokinase 2-driven glycolysis in pericytes activates their contractility leading to tumor blood vessel abnormalities.

Defective pericyte-endothelial cell interaction in tumors leads to a chaotic, poorly organized and dysfunctional vasculature. However, the underlying mechanism behind this is poorly studied. Herein, we develop a method that combines magnetic beads and flow cytometry cell sorting to isolate pericytes from tumors and normal adjacent tissues from patients with non-small cell lung cancer (NSCLC) and hepatocellular carcinoma (HCC). Pericytes from tumors show defective blood vessel supporting functions when comparing to those obtained from normal tissues. Mechanistically, combined proteomics and metabolic flux analysis reveals elevated hexokinase 2(HK2)-driven glycolysis in tumor pericytes, which up-regulates their ROCK2-MLC2 mediated contractility leading to impaired blood vessel supporting function. Clinically, high percentage of HK2 positive pericytes in blood vessels correlates with poor patient overall survival in NSCLC and HCC. Administration of a HK2 inhibitor induces pericyte-MLC2 driven tumor vasculature remodeling leading to enhanced drug delivery and efficacy against tumor growth. Overall, these data suggest that glycolysis in tumor pericytes regulates their blood vessel supporting role.

Vascular and Lymphatic Malformations: Perspectives From Human and Vertebrate Studies.

Vascular malformations, affecting ≈1% to 1.5% of the population, comprise a spectrum of developmental patterning defects of capillaries, arteries, veins, and/or lymphatics. The majority of vascular malformations occur sporadically; however, inherited malformations exist as a part of complex congenital diseases. The malformations, ranging from birthmarks to life-threatening conditions, are present at birth, but may reveal signs and symptoms-including pain, bleeding, disfigurement, and functional defects of vital organs-in infancy, childhood, or adulthood. Vascular malformations often exhibit recurrent patterns at affected sites due to the lack of curative treatments. This review series provides a state-of-the-art assessment of vascular malformation research at basic, clinical, genetic, and translational levels.

Genetic Basis and Therapies for Vascular Anomalies.

Vascular and lymphatic malformations represent a challenge for clinicians. The identification of inherited and somatic mutations in important signaling pathways, including the PI3K (phosphoinositide 3-kinase)/AKT (protein kinase B)/mTOR (mammalian target of rapamycin), RAS (rat sarcoma)/RAF (rapidly accelerated fibrosarcoma)/MEK (mitogen-activated protein kinase kinase)/ERK (extracellular signal-regulated kinases), HGF (hepatocyte growth factor)/c-Met (hepatocyte growth factor receptor), and VEGF (vascular endothelial growth factor) A/VEGFR (vascular endothelial growth factor receptor) 2 cascades has led to the evaluation of tailored strategies with preexisting cancer drugs that interfere with these signaling pathways. The era of theranostics has started for the treatment of vascular anomalies. Registration: URL: https://www.clinicaltrialsregister.eu; Unique identifier: 2015-001703-32.

Off-Label Use and Safety of Drug Use in Vascular Anomalies.

BACKGROUND: Off-label drug use is associated with an increased risk of adverse drug reactions. It is common in pediatrics and in rare diseases, which are two characteristics applying to vascular anomalies (VA). OBJECTIVES: The aim of this work was to quantify off-label drug use in VA and assess its safety. METHODS: A review was conducted to extract a list of drugs used in VA management. A drug was considered to have significant safety concerns if a black box warning was present or if a serious adverse drug reaction (SADR) was reported in at least 1% of the patients (SADR is defined as a noxious and unintended response to a drug that occurs at any dose and results in hospitalization, prolongation of existing hospitalization, congenital malformation, persistent or significant disability or incapacity, life-threatening condition, or death). The labelling status and safety of each drug was assessed based on the product monograph, Micromedex, and the FDA data. RESULTS: We found that 98.9% of the inventoried drugs were used off-label or unlicensed for VA management. Only the oral solution of propranolol hydrochloride (Hemangeol®) for the treatment of infantile hemangiomas is approved. Significant safety issues concerned 73% of the drugs and were more frequent among systemic than locally delivered drugs. CONCLUSIONS: Off-label drug use in VA is the rule and not the exception. Significant safety concerns are common. It is necessary to carefully weigh risk and benefits for every patient when using systemic and local treatments carrying safety concerns. Patients should be openly informed and involved in the decision-making process.

Impact of vascular abnormality on contrast-enhanced CT and high C-reactive protein levels on postoperative pancreatic hemorrhage after pancreaticoduodenectomy: A multi-institutional, retrospective analysis of 590 consecutive cases.

BACKGROUND: /Objectives: This study aimed to elucidate the efficacy of CT findings and perioperative characteristics to predict post-pancreatectomy hemorrhage (PPH): a critical complication after pancreaticoduodenectomy. METHODS: The records of 590 consecutive patients who underwent pancreaticoduodenectomy at three institutes between 2012 and 2018 were included. The presence of a vascular wall abnormality or ascites with high density (vascular abnormality) on postoperative day (POD) 5-10 contrast-enhanced CT (early CT), perioperative characteristics, and any PPH or pseudoaneurysm formation (PPH events) were analyzed through a multivariate analysis. RESULTS: PPH events occurred in 48 out of 590 patients (8%). The vascular abnormality on early CT and the C-reactive protein (CRP) value on POD 3 were independent risk factors for PPH events after POD5 (vascular abnormality: odds ratio 6.42, p = 0.001; CRP on POD 3: odds ratio 1.17, p = 0.016). The sensitivity of vascular abnormality for PPH events was 24% (7/29), and the positive predictive value was 30% (7/23). The combination of vascular abnormality and a high CRP value (≥15.5 mg/dL) on postoperative day 3 had a higher positive predictive value of 64% (7/11) than the vascular abnormality alone. None of the seven PPH events that occurred more than one month after surgery were foreseen via early CT. CONCLUSION: The combination of vascular abnormality and high CRP value was associated with increasing risk of PPH events after pancreaticoduodenectomy, but the low sensitivity of early CT must be noted as an important shortcoming. The normal findings on early CT could not eliminate the risk of late PPH.

How I do it: Subtemporal transtentorial approach for cavernous malformation of the pons.

BACKGROUND: Removal of a pontine cavernous malformation requires sufficient exposure since any restriction on surgical freedom may lead to suboptimal visualization of the lesion, injury to the brainstem, and neurological catastrophe. METHODS: We describe and demonstrate the subtemporal transtentorial approach to a cavernous malformation of the upper pons, with emphasis on adequate surgical exposure while avoiding the need for extensive bone removal of the skull base. CONCLUSIONS: The meticulous technique is paramount to the successful removal of any brainstem cavernous malformation. Along with the surgical exposure, delicate handling of the malformation is demonstrated in the accompanying operative video.

Cardiac Neural Crest Cells: Their Rhombomeric Specification, Migration, and Association with Heart and Great Vessel Anomalies.

Outflow tract abnormalities are the most frequent congenital heart defects. These are due to the absence or dysfunction of the two main cell types, i.e., neural crest cells and secondary heart field cells that migrate in opposite directions at the same stage of development. These cells directly govern aortic arch patterning and development, ascending aorta dilatation, semi-valvular and coronary artery development, aortopulmonary septation abnormalities, persistence of the ductus arteriosus, trunk and proximal pulmonary arteries, sub-valvular conal ventricular septal/rotational defects, and non-compaction of the left ventricle. In some cases, depending on the functional defects of these cells, additional malformations are found in the expected spatial migratory area of the cells, namely in the pharyngeal arch derivatives and cervico-facial structures. Associated non-cardiovascular anomalies are often underestimated, since the multipotency and functional alteration of these cells can result in the modification of multiple neural, epidermal, and cervical structures at different levels. In most cases, patients do not display the full phenotype of abnormalities, but congenital cardiac defects involving the ventricular outflow tract, ascending aorta, aortic arch and supra-aortic trunks should be considered as markers for possible impaired function of these cells. Neural crest cells should not be considered as a unique cell population but on the basis of their cervical rhombomere origins R3-R5 or R6-R7-R8 and specific migration patterns: R3-R4 towards arch II, R5-R6 arch III and R7-R8 arch IV and VI. A better understanding of their development may lead to the discovery of unknown associated abnormalities, thereby enabling potential improvements to be made to the therapeutic approach.

Management of disseminated intravascular coagulation associated with aortic aneurysm and vascular malformations.

Aortic aneurysms and vascular malformations are sometimes associated with disseminated intravascular coagulation (DIC). A typical blood coagulation test shows decrease in platelet count and fibrinogen, and increases in fibrin/fibrinogen degradation products (FDP) and D-dimer. The coagulation activation marker thrombin-antithrombin complex (TAT) and the fibrinolysis activation marker plasmin-α2 plasmin inhibitor (PIC) are significantly increased. α2 plasmin inhibitor (α2PI) is significantly reduced. Since no prolongation of prothrombin time (PT) is noticeable and activated partial thromboplastin time (APTT) is shortened in some cases, DIC cannot be diagnosed or ruled out by PT and APTT alone. The cornerstone of treatment for DIC is to treat the underlying disease. However, surgery is not possible in some cases. Follow-up may be appropriate in patients with abnormal results from coagulation tests and no bleeding. However, pharmacotherapy is often required in cases with bleeding. Unfractionated heparin, low molecular weight heparin, protease inhibitors, recombinant thrombomodulin, direct oral anticoagulants, and factor XIII preparations are effective. If PIC is significantly increased and α2PI is significantly decreased, or if the bleeding is severe, tranexamic acid is used as an antifibrinolytic therapy with anticoagulant therapy. In such cases, attention should be paid not only to TAT but also changes in PIC.

Tracking down the White Plague. Chapter two: The role of endocranial abnormal blood vessel impressions and periosteal appositions in the paleopathological diagnosis of tuberculous meningitis.

Although endocranial abnormal blood vessel impressions (ABVIs) and periosteal appositions (PAs) have been considered as paleopathological diagnostic criteria for tuberculous meningitis (TBM) based on findings of previous studies, they are not pathognomonic for tuberculosis (TB). Therefore, their utilization in the paleopathological practice can be questioned, especially in consideration that most of the previous studies were not performed on identified skeletal collections but on osteoarchaeological material and did not include statistical data analysis. To fill the aforementioned research gap, for the first time, a macroscopic investigation was conducted on identified pre-antibiotic era skeletons from the Terry Collection. A sample set of 234 individuals who died of TB (TB group) and 193 individuals who died of non-tuberculous causes (NTB group) were examined. The frequency of ABVIs and PAs, as well as other probable TB-related lesions was recorded. To determine the significance of difference (if any) in the frequencies of ABVIs and PAs between the two groups, χ2 testing of our data was performed. We found that ABVIs, PAs, and their co-occurrence with each other and with other probable TB-related lesions were more common in the TB group than in the NTB group. In addition, the χ2 comparative frequencies of ABVIs and PAs revealed a statistically significant difference between individuals who died of TB and individuals who died of NTB causes. Our findings strengthen those of previous studies that ABVIs and PAs are not specific to TBM but can be of tuberculous origin. Therefore, they do have a diagnostic value in the identification of TB in human osteoarchaeological material, especially when they simultaneously occur with other probable TB-related lesions. Their prudent utilization provides paleopathologists with a stronger basis for diagnosing TB and consequently, a more sensitive means of assessing TB frequency in past human populations.

Diagnosis and treatment of pure arterial malformation: Three case reports and literature review.

RATIONALE: The incidence of pure arterial malformations is relatively low, and few cases have been reported. Only 2 cases with pure arterial malformation have been reported to receive surgery or endovascular treatment. PATIENT CONCERNS: We report 3 cases and review the relevant literatures. The head examinations of the patients suggested the presence of high-density shadows in front of the pons and midbrain, the dilation of the supraclinoid segment of the right internal carotid artery, and moyamoya in the left brain with an aneurysm-like expansion located on the left posterior communicating artery respectively. After admission, head digital subtraction angiography (DSA) was performed. DIAGNOSES: Digital subtraction angiography (DSA) for these 3 patients showed that the left posterior communicating artery, the supraclinoid segment of the right internal carotid artery, and the left posterior communicating artery appeared dilated, tortuous, and spirally elongated. In addition, the lesions in the latter 2 patients were accompanied with local aneurysmal changes. INTERVENTIONS: Two patients were given conservative treatment, and another patient was given endovascular treatment. A head DSA was reviewed 6 months after therapy. OUTCOMES: The prognosis status of the 3 patients was good. Two patients in the conservative treatment group showed no changes in the lesions on head DSA examination. The DSA examination of the third patient indicated that the vascular remodeling of the diseased vessels was good, the blood vessels were unobstructed, and the aneurysms had disappeared. LESSONS: Pure arterial malformations mostly occur in young women and may involve any blood vessels in the brain. It can be accompanied with local aneurysms and calcification. The patients are often given conservative treatment but need to be reviewed regularly. However, it is beneficial to give endovascular treatment to the patients with local aneurysms.

Emerging importance of molecular pathogenesis of vascular malformations in clinical practice and classifications.

Vascular malformations occur during early vascular development resulting in abnormally formed vessels that can manifest as arterial, venous, capillary or lymphatic lesions, or in combination, and include local tissue overdevelopment. Vascular malformations are largely caused by sporadic somatic gene mutations. This article aims to review and discuss current molecular signaling pathways and therapeutic targets for vascular malformations and to classify vascular malformations according to the molecular pathways involved. A literature review was performed using Embase and Medline. Different MeSH terms were combined for the search strategy, with the aim of encompassing all studies describing the classification, pathogenesis, and treatment of vascular malformations. Major pathways involved in the pathogenesis of vascular malformations are vascular endothelial growth factor (VEGF), Ras/Raf/MEK/ERK, angiopoietin-TIE2, transforming growth factor beta (TGF-ß), and PI3K/AKT/mTOR. These pathways are involved in controlling cellular growth, apoptosis, differentiation, and proliferation, and play a central role in endothelial cell signaling and angiogenesis. Many vascular malformations share similar aberrant molecular signaling pathways with cancers and inflammatory disorders. Therefore, selective anticancer agents and immunosuppressants may be beneficial in treating vascular malformations of specific mutations. The current classification systems of vascular malformations, including the International Society of the Study of Vascular Anomalies (ISSVA) classification, are primarily observational and clinical, and are not based on the molecular pathways involved in the pathogenesis of the condition. Several molecular pathways with potential therapeutic targets have been demonstrated to contribute to the development of various vascular anomalies. Classifying vascular malformations based on their molecular pathogenesis may improve treatment by determining the underlying nature of the condition and their potential therapeutic target.

Blood Pressure Management Following Large Vessel Occlusion Strokes: A Narrative Review

Stroke is one of the leading causes of morbidity and mortality worldwide. Intravenous tissue plasminogen activator and mechanical thrombectomy comprise the two major treatments for acute ischemic stroke. Tissue plasminogen activator has been used for more than two decades and guidelines for hemodynamic management following tissue plasminogen activator administration are well established. However, mechanical thrombectomy is a relatively newer therapy and there is a paucity of evidence regarding hemodynamic management following large vessel occlusion strokes. The important tenets guiding the pathophysiology of large vessel occlusion strokes include understanding of cerebral autoregulation, collateral circulation, and blood pressure variability. In this narrative review, we discuss the current American Heart Association-American Stroke Association guidelines for the early management of acute ischemic stroke during different phases of the illness, encountered at different sections of a hospital including the emergency room, the neuro-interventional suite, and the intensive care unit. There is emerging evidence with regard to post-recanalization blood pressure management following large vessel occlusion strokes. Future research directions will include rea-ltime blood pressure variability assessments, identifying the extent of impaired autoregulation, and providing guidelines related to range and personalized blood pressure trajectories for patients following large vessel occlusion strokes.

The Noonan Syndrome Gene Lztr1 Controls Cardiovascular Function by Regulating Vesicular Trafficking.

RATIONALE: Noonan syndrome (NS) is one of the most frequent genetic disorders. Bleeding problems are among the most common, yet poorly defined complications associated with NS. A lack of consensus on the management of bleeding complications in patients with NS indicates an urgent need for new therapeutic approaches. OBJECTIVE: Bleeding disorders have recently been described in patients with NS harboring mutations of LZTR1 (leucine zipper-like transcription regulator 1), an adaptor for CUL3 (CULLIN3) ubiquitin ligase complex. Here, we assessed the pathobiology of LZTR1-mediated bleeding disorders. METHODS AND RESULTS: Whole-body and vascular specific knockout of Lztr1 results in perinatal lethality due to cardiovascular dysfunction. Lztr1 deletion in blood vessels of adult mice leads to abnormal vascular leakage. We found that defective adherent and tight junctions in Lztr1-depleted endothelial cells are caused by dysregulation of vesicular trafficking. LZTR1 affects the dynamics of fusion and fission of recycling endosomes by controlling ubiquitination of the ESCRT-III (endosomal sorting complex required for transport III) component CHMP1B (charged multivesicular protein 1B), whereas NS-associated LZTR1 mutations diminish CHMP1B ubiquitination. LZTR1-mediated dysregulation of CHMP1B ubiquitination triggers endosomal accumulation and subsequent activation of VEGFR2 (vascular endothelial growth factor receptor 2) and decreases blood levels of soluble VEGFR2 in Lztr1 haploinsufficient mice. Inhibition of VEGFR2 activity by cediranib rescues vascular abnormalities observed in Lztr1 knockout mice Conclusions: Lztr1 deletion phenotypically overlaps with bleeding diathesis observed in patients with NS. ELISA screening of soluble VEGFR2 in the blood of LZTR1-mutated patients with NS may predict both the severity of NS phenotypes and potential responders to anti-VEGF therapy. VEGFR inhibitors could be beneficial for the treatment of bleeding disorders in patients with NS.

Mutations in RPSA and NKX2-3 link development of the spleen and intestinal vasculature.

Idiopathic intestinal varicosis is a developmental disorder defined by dilated and convoluted submucosal veins in the colon or small bowel. A limited number of families with idiopathic intestinal varices has been reported, but the genetic cause has not yet been identified. We performed whole-exome and targeted Sanger sequencing of candidate genes in five intestinal varicosis families. In four families, mutations in the RPSA gene were found, a gene previously linked to congenital asplenia. Individuals in these pedigrees had intestinal varicose veins and angiodysplasia, often in combination with asplenia. In a further four-generation pedigree that only showed intestinal varicosities, the RPSA gene was normal. Instead, a nonsense mutation in the homeobox gene NKX2-3 was detected which cosegregated with the disease in this large family with a LOD (logarithm of the odds) score of 3.3. NKX2-3 is a component of a molecular pathway underlying spleen and gut vasculature development in mice. Our results provide a molecular basis for familial idiopathic intestinal varices. We provide evidence for a relationship between the molecular pathways underlying the development of the spleen and intestinal mucosal vasculature that is conserved between humans and mice. We propose that clinical management of intestinal varices, should include assessment of a functional spleen.

Sclerotherapy of benign oral vascular lesions with non-diluted ethanolamine oleate / Escleroterapia de lesiones vasculares orales benignas con oleato de etanolamina no diluido

Benign oral vascular lesions are anomalies characterized by the blood vessels proliferation or malformation and the treatment with the sclerosing agent ethanolamine oleate acts irrigating the vessel producing a sterile inflammatory response. The objective of this study was to report and discuss the results from treatment of benign oral vascular lesions with non-diluted ethanolamine oleate through the analysis of clinical records. The sample was composed by the selection of twenty-six patients (12 male and 14 female), with oral vascular malformations. All lesions were treated with intralesional injections of undiluted ethanolamine oleate. These patients attended in Oral Medicine outpatient clinic of the Federal University of Paraná between the years of 2011 to 2015. The average age was 60.65 years, with a higher prevalence for women. The majority of the individuals had one lesion and its location was mostly in the lower lip. The main complaint was about a physical discomfort. The lesions had the average size of 6.52 mm and received a median number of 2.32 applications. Only one patient reported feeling pain in the postoperative week. In most cases the resolution of the lesion was considered partial. Follow-up was obtained up to one month after the end of treatment. The sclerotherapy with undiluted ethanolamine oleate shows acceptable results in the treatment of small benign oral vascular lesions with a few minor side effects.

Las lesiones vasculares orales benignas son anomalías caracterizadas por la proliferación o malformación de los vasos sanguíneos y el tratamiento con el agente esclerosante etanolamina oleato actúa irrigando el vaso produciendo una respuesta inflamatoria estéril. El objetivo de este estudio fue informar y discutir los resultados del tratamiento de lesiones vasculares orales benignas con oleato de etanolamina no diluido a través del análisis de historias clínicas. La muestra estuvo compuesta por la selección de veintiséis pacientes (12 hombres y 14 mujeres), con malformaciones vasculares orales. Todas las lesiones fueron tratadas con inyecciones intralesionales de oleato de etanolamina sin diluir. Estos pacientes acudieron a la clínica ambulatoria de Medicina Oral de la Universidad Federal de Paraná entre los años 2011 a 2015. La edad promedio fue de 60,65 años, con una mayor prevalencia para las mujeres. La mayoría de los individuos tenían una lesión y su ubicación era principalmente en el labio inferior. La queja principal era sobre una molestia física. Las lesiones tenían un tamaño promedio de 6,52 mm y recibieron una mediana de 2,32 aplicaciones. Solo un paciente informó haber sentido dolor en la semana postoperatoria. En la mayoría de los casos, la resolución de la lesión se consideró parcial. El seguimiento se obtuvo hasta un mes después del final del tratamiento. La escleroterapia con oleato de etanolamina sin diluir muestra resultados aceptables en el tratamiento de pequeñas lesiones vasculares orales benignas con algunos efectos secundarios menores.

CDC42 Deletion Elicits Cerebral Vascular Malformations via Increased MEKK3-Dependent KLF4 Expression.

RATIONALE: Aberrant formation of blood vessels precedes a broad spectrum of vascular complications; however, the cellular and molecular events governing vascular malformations are not yet fully understood. OBJECTIVE: Here, we investigated the role of CDC42 (cell division cycle 42) during vascular morphogenesis and its relative importance for the development of cerebrovascular malformations. METHODS AND RESULTS: To avoid secondary systemic effects often associated with embryonic gene deletion, we generated an endothelial-specific and inducible knockout approach to study postnatal vascularization of the mouse brain. Postnatal endothelial-specific deletion of Cdc42 elicits cerebrovascular malformations reminiscent of cerebral cavernous malformations (CCMs). At the cellular level, loss of CDC42 function in brain endothelial cells (ECs) impairs their sprouting, branching morphogenesis, axial polarity, and normal dispersion within the brain tissue. Disruption of CDC42 does not alter EC proliferation, but malformations occur where EC proliferation is the most pronounced during brain development-the postnatal cerebellum-indicating that a high, naturally occurring EC proliferation provides a permissive state for the appearance of these malformations. Mechanistically, CDC42 depletion in ECs elicited increased MEKK3 (mitogen-activated protein kinase kinase kinase 3)-MEK5 (mitogen-activated protein kinase kinase 5)-ERK5 (extracellular signal-regulated kinase 5) signaling and consequent detrimental overexpression of KLF (Kruppel-like factor) 2 and KLF4, recapitulating the hallmark mechanism for CCM pathogenesis. Through genetic approaches, we demonstrate that the coinactivation of Klf4 reduces the severity of vascular malformations in Cdc42 mutant mice. Moreover, we show that CDC42 interacts with CCMs and that CCM3 promotes CDC42 activity in ECs. CONCLUSIONS: We show that endothelial-specific deletion of Cdc42 elicits CCM-like cerebrovascular malformations and that CDC42 is engaged in the CCM signaling network to restrain the MEKK3-MEK5-ERK5-KLF2/4 pathway.

Placental vascular abnormalities in the mouse alter umbilical artery wave reflections.

Current methods to detect placental vascular pathologies that monitor Doppler ultrasound changes in umbilical artery (UA) pulsatility have only moderate diagnostic utility, particularly in late gestation. In fetal mice, we recently demonstrated that reflected pressure waves propagate counter to the direction of flow in the UA and proposed the measurement of these reflections as a means to detect abnormalities in the placental circulation. In the present study, we used this approach in combination with microcomputed tomography to investigate the relationship between altered placental vascular architecture and changes in UA wave reflection metrics. Fetuses were assessed at embryonic day (E) 15.5 and E17.5 in control C57BL6/J mice and dams treated with combination antiretroviral therapy (cART), a known model of fetal growth restriction. Whereas the reflection coefficient was not different between groups at E15.5, it was 27% higher at E17.5 in cART-treated mice compared with control mice. This increase in reflection coefficient corresponded to a 36% increase in the total number of vessel segments, a measure of overall architectural complexity. Interestingly, there was no difference in UA pulsatility index between groups, suggesting that the wave reflections convey information about vascular architecture that is not captured by conventional ultrasound metrics. The wave reflection parameters were found to be associated with the morphology of the fetoplacental arterial tree, with the area ratio between the UA and first branch points correlating with the reflection coefficient. This study highlights the potential for wave reflection to aid in the noninvasive clinical assessment of placental vascular pathology. NEW & NOTEWORTHY We used a novel ultrasound methodology based on detecting pulse pressure waves that propagate along the umbilical artery to investigate the relationship between changes in wave reflection metrics and altered placental vascular architecture visualized by microcomputed tomography. Using pregnant mice treated with combination antiretroviral therapy, a model of fetal growth restriction, we demonstrated that reflections in the umbilical artery are sensitive to placental vascular abnormalities and associated with the geometry of the fetoplacental tree.