GI-Associated Hemangiomas and Vascular Malformations.
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ABSTRACT:
SUBMITTER: Yoo S
PROVIDER: S-EPMC3311506 | biostudies-other | 2011 Sep
REPOSITORIES: biostudies-other
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Project description:Vascular malformations (VMs) comprise a wide spectrum of lesions that are classified by content and flow characteristics. These lesions, occurring in both focal and diffuse forms, can involve any organ and tissue plane and can cause significant morbidity in both children and adults. Since treatment strategy depends on the type of malformation, correct diagnosis and classification of a vascular lesion are crucial. Slow-flow VMs (venous and lymphatic malformations) are often treated by sclerotherapy, whereas fast-flow lesions (arteriovenous malformations) are generally managed with embolization. In addition, some cases of VMs are best treated surgically. This review will present an overview of VMs in the female pelvis as well as a discussion of endovascular therapeutic techniques.
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Project description:Identification and treatment of vascular malformations is a challenging endeavor for physicians, especially given the great concern and anxiety created for patients and their families. The goal of this article is to provide a review of vascular malformations, organized by subtype, including capillary, venous, lymphatic and arteriovenous malformations. Only by developing a clear understanding of the clinical aspects, diagnostic tools, imaging modalities, and options for intervention will appropriate care be provided and results maximized.
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Project description:BackgroundVascular malformations in the central nervous system are difficult to monitor and treat due to their inaccessible location. Angiogenic and inflammatory proteins are secreted into the bloodstream and may serve as useful biomarkers for identifying patients at risk for complications or with certain disease phenotypes.MethodsA validated multiplex protein array consisting of 26 angiogenic and inflammatory biomarkers (Angiome) was assessed in plasma isolated from healthy controls and patients with either sporadic brain arteriovenous malformation (BAVM), familial cerebral cavernous malformation (CCM), or hereditary hemorrhagic telangiectasia (HHT). These samples were obtained from archives of ongoing research studies at the University of California San Francisco and through prospective collection at the Toronto HHT Centre at St. Michael's Hospital.ResultsWe compared circulating biomarker levels from each patient group to healthy controls and analyzed each pairwise combination of patient groups for differences in biomarker levels. Additionally, we analyzed the HHT samples to determine the association between biomarker levels and the following HHT-specific phenotypes, BAVM, pulmonary arteriovenous malformation (PAVM), liver vascular malformation (LVM), and gastrointestinal (GI) bleeding. Compared to controls, levels of SDF1 were significantly elevated in HHT patients (Proportional Increase [PI] = 1.87, p < 0.001, q = 0.011). Levels of sENG were significantly reduced in HHT patients compared to controls (PI = 0.56, p < 0.001, q < 0.001), reflecting the prevalence of HHT1 patients in this cohort. Levels of IL6 (PI = 3.22, p < 0.001, q < 0.001) and sTGFβR3 (PI = 0.70, p = 0.001, q < 0.029) differed significantly in CCM patients compared to controls. Compared to controls, ten of the biomarkers were significantly different in sporadic BAVM patients (q-values < 0.05). Among the pairwise combinations of patient groups, a significant elevation was observed in TGFβ1 in CCM patients compared to sporadic BAVM patients (PI = 2.30, p < 0.001, q = 0.034). When examining the association of circulating biomarker levels with HHT-specific phenotypes, four markers were significantly lower in HHT patients with BAVM (q-values < 0.05), and four markers were significantly higher in patients with LVM (q-values < 0.05).ConclusionsThis pilot study suggests that the profile of circulating angiogenic and inflammatory biomarkers may be unique to each type of vascular malformation. Furthermore, this study indicates that circulating biomarkers may be useful for assessing phenotypic traits of vascular malformations.
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Project description:Patients with the familial form of cerebral cavernous malformations (CCMs) are haploinsufficient for the CCM1, CCM2, or CCM3 gene. Loss of corresponding CCM proteins increases RhoA kinase-mediated endothelial permeability in vitro, and in mouse brains in vivo. A prospective case-controlled observational study investigated whether the brains of human subjects with familial CCM show vascular hyperpermeability by dynamic contrast-enhanced quantitative perfusion magnetic resonance imaging, in comparison with CCM cases without familial disease, and whether lesional or brain vascular permeability correlates with CCM disease activity. Permeability in white matter far (WMF) from lesions was significantly greater in familial than in sporadic cases, but was similar in CCM lesions. Permeability in WMF increased with age in sporadic patients, but not in familial cases. Patients with more aggressive familial CCM disease had greater WMF permeability compared to those with milder disease phenotype, but similar lesion permeability. Subjects receiving statin medications for routine cardiovascular indications had a trend of lower WMF, but not lesion, permeability. This is the first demonstration of brain vascular hyperpermeability in humans with an autosomal dominant disease, as predicted mechanistically. Brain permeability, more than lesion permeability, may serve as a biomarker of CCM disease activity, and help calibrate potential drug therapy.
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Project description:Misdiagnosis of phosphatase and tensin homologue hamartoma syndromes is common. Correct diagnosis has a relevant impact on patients, as the risk of malignancies is high and treatment options are limited. We report the case of a 24-year-old man who presented with symptomatic vascular intramuscular lesions of the left forearm and right calf, macrocephaly, post Hashimoto thyroiditis, a multicystic intracranial paratrigonal lesion, lentiginous hyperpigmented maculae on the foreskin and multiple skin lesions. MRI showed extended fibrofatty changes and malformed vessels in the forearm and calf lesions, also, arteriovenous shunting was present in these lesions. The patient had been treated by embolisation and surgically in the past, with limited results. A multidisciplinary assessment and genetic counselling were undertaken and a surveillance programme was initiated. Treatment options of the symptomatic vascular lesions include excision or possibly cryoablation. Physiotherapy to prevent progression of the contractures should be initiated meanwhile.
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Project description:BackgroundVariants in the LZTR1 (leucine-zipper-like transcription regulator 1) gene (OMIM #600574) have been reported in recessive Noonan syndrome patients. In vivo evidence from animal models to support its causative role is lacking.MethodsBy CRISPR-Cas9 genome editing, we generated lztr1-mutated zebrafish (Danio rerio). Analyses of histopathology and downstream signaling were performed to investigate the pathogenesis of cardiac and extracardiac abnormalities in Noonan syndrome.ResultsA frameshift deletion allele was created in the zebrafish lztr1. Crosses of heterozygotes obtained homozygous lztr1 null mutants that modeled LZTR1 loss-of-function. Histological analyses of the model revealed ventricular hypertrophy, the deleterious signature of Noonan syndrome-associated cardiomyopathy. Further, assessment for extracardiac abnormalities documented multiple vascular malformations, resembling human vascular pathology caused by RAS/MAPK activation. Due to spatiotemporal regulation of LZTR1, its downstream function was not fully elucidated from western blots of adult tissue.ConclusionOur novel zebrafish model phenocopied human recessive Noonan syndrome and supported the loss-of-function mechanism of disease-causing LZTR1 variants. The discovery of vascular malformations in mutants calls for the clinical follow-up of patients to monitor for its emergence. The model will serve as a novel platform for investigating the pathophysiology linking RAS/MAPK signaling to cardiac and vascular pathology.
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Project description:This review discusses recent research on the genetic, molecular, cellular, and developmental mechanisms underlying the etiology of vascular malformations of the brain (VMBs), including cerebral cavernous malformation, sporadic brain arteriovenous malformation, and the arteriovenous malformations of hereditary hemorrhagic telangiectasia. Summary of Review- The identification of gene mutations and genetic risk factors associated with cerebral cavernous malformation, hereditary hemorrhagic telangiectasia, and sporadic arteriovenous malformation has enabled the development of animal models for these diseases and provided new insights into their etiology. All of the genes associated with VMBs to date have known or plausible roles in angiogenesis and vascular remodeling. Recent work suggests that the angiogenic process most severely disrupted by VMB gene mutation is that of vascular stabilization, the process whereby vascular endothelial cells form capillary tubes, strengthen their intercellular junctions, and recruit smooth muscle cells to the vessel wall. In addition, there is now good evidence that in some cases, cerebral cavernous malformation lesion formation involves a genetic 2-hit mechanism in which a germline mutation in one copy of a cerebral cavernous malformation gene is followed by a somatic mutation in the other copy. There is also increasing evidence that environmental second hits can produce lesions when there is a mutation to a single allele of a VMB gene.Recent findings begin to explain how mutations in VMB genes render vessels vulnerable to rupture when challenged with other inauspicious genetic or environmental factors and have suggested candidate therapeutics. Understanding of the cellular mechanisms of VMB formation and progression in humans has lagged behind that in animal models. New knowledge of lesion biology will spur new translational work. Several well-established clinical and genetic database efforts are already in place, and further progress will be facilitated by collaborative expansion and standardization of these.
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Project description:Children with vascular malformations are best managed with a multidisciplinary team of specialists. Interventional radiology may deliver primary treatment such as staged sclerotherapy and embolization for malformations that are poor candidates for primary surgical resection or play a supportive role such as preoperative or intraoperative embolization. A thorough understanding of vascular morphology and flow dynamics is imperative to choosing the best treatment tool and technique. In this review, the author discusses the selection of techniques and tools used to treat vascular malformations based on their angiographic morphology.
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Project description:Mosaic inactivation of CCM2 in humans causes cerebral cavernous malformations (CCMs) containing adjacent dilated blood-filled multi-cavernous lesions. We used CRISPR-Cas9 mutagenesis to induce mosaic inactivation of zebrafish ccm2 resulting in a novel lethal multi-cavernous lesion in the embryonic caudal venous plexus (CVP) caused by obstruction of blood flow by intraluminal pillars. These pillars mimic those that mediate intussusceptive angiogenesis; however, in contrast to the normal process, the pillars failed to fuse to split the pre-existing vessel in two. Abortive intussusceptive angiogenesis stemmed from mosaic inactivation of ccm2 leading to patchy klf2a overexpression and resultant aberrant flow signaling. Surviving adult fish manifested histologically typical hemorrhagic CCM. Formation of mammalian CCM requires the flow-regulated transcription factor KLF2; fish CCM and the embryonic CVP lesion failed to form in klf2a null fish indicating a common pathogenesis with the mammalian lesion. These studies describe a zebrafish CCM model and establish a mechanism that can explain the formation of characteristic multi-cavernous lesions.
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Project description:Patients with hereditary hemorrhagic telangiectasia (HHT) have arteriovenous malformations (AVMs) with genetic mutations involving the activin-A receptor like type 1 (ACVRL1 or ALK1) and endoglin (ENG). Recent studies have shown that Neuropilin-1 (NRP-1) inhibits ALK1. We investigated the expression of NRP-1 in livers of patients with HHT and found that there was a significant reduction in NRP-1 in perivascular smooth muscle cells (SMCs). We used Nrp1SM22KO mice (Nrp1 was ablated in SMCs) and found hemorrhage, increased immune cell infiltration with a decrease in SMCs, and pericyte lining in lungs and liver in adult mice. Histologic examination revealed lung arteriovenous fistulas (AVFs) with enlarged liver vessels. Evaluation of the retina vessels at P5 from Nrp1SM22KO mice demonstrated dilated capillaries with a reduction of pericytes. In inflow artery of surgical AVFs from the Nrp1SM22KO versus WT mice, there was a significant decrease in Tgfb1, Eng, and Alk1 expression and phosphorylated SMAD1/5/8 (pSMAD1/5/8), with an increase in apoptosis. TGF-β1-stimulated aortic SMCs from Nrp1SM22KO versus WT mice have decreased pSMAD1/5/8 and increased apoptosis. Coimmunoprecipitation experiments revealed that NRP-1 interacts with ALK1 and ENG in SMCs. In summary, NRP-1 deletion in SMCs leads to reduced ALK1, ENG, and pSMAD1/5/8 signaling and reduced cell death associated with AVM formation.
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