Pathogenesis Of Vascular Malformations Research Articles

Vascular Malformations

Abstract Vascular malformations are intricate anomalies of the circulatory system, presenting a diverse array of clinical manifestations, and posing significant challenges in diagnosis and treatment. The pathogenesis of vascular malformations is explored through the lens of genetic and molecular mechanisms, shedding light on the pivotal role of somatic mutations and dysregulated signaling pathways. Clinical presentations of vascular malformations are widely variable, ranging from cosmetic concerns to life-threatening complications. The utility of imaging techniques, such as magnetic resonance imaging (MRI), computed tomography (CT), and angiography, are discussed in detail, emphasizing their role in precise delineation and characterization. Therapeutic strategies for vascular malformations are multifaceted, considering factors such as lesion size, location, potential complications, and patient-specific factors. Traditional interventions, including surgical excision and embolization, are appraised alongside emerging approaches like targeted molecular therapies and minimally invasive procedures. The manuscript underscores the need for an individualized treatment approach, optimizing outcomes while minimizing risks and complications. In summation, this manuscript offers a comprehensive analysis of vascular malformations, encompassing their underlying pathogenesis, clinical nuances, diagnostic methods, and therapeutic considerations. By synthesizing current knowledge and highlighting gaps in understanding, this review serves as a valuable resource for clinicians, researchers, and medical practitioners, fostering an enhanced comprehension of vascular malformations and paving the way for improved patient care and innovative research endeavors.

Induced Endothelial Cell Cycle Arrest Prevents Arteriovenous Malformations in Hereditary Hemorrhagic Telangiectasia.

Distinct endothelial cell cycle states (early G1 versus late G1) provide different "windows of opportunity" to enable the differential expression of genes that regulate venous versus arterial specification, respectively. Endothelial cell cycle control and arteriovenous identities are disrupted in vascular malformations including arteriovenous shunts, the hallmark of hereditary hemorrhagic telangiectasia (HHT). To date, the mechanistic link between endothelial cell cycle regulation and the development of arteriovenous malformations (AVMs) in HHT is not known. We used BMP (bone morphogenetic protein) 9/10 blocking antibodies and endothelial-specific deletion of activin A receptor like type 1 (Alk1) to induce HHT in Fucci (fluorescent ubiquitination-based cell cycle indicator) 2 mice to assess endothelial cell cycle states in AVMs. We also assessed the therapeutic potential of inducing endothelial cell cycle G1 state in HHT to prevent AVMs by repurposing the Food and Drug Administration-approved CDK (cyclin-dependent kinase) 4/6 inhibitor (CDK4/6i) palbociclib. We found that endothelial cell cycle state and associated gene expressions are dysregulated during the pathogenesis of vascular malformations in HHT. We also showed that palbociclib treatment prevented AVM development induced by BMP9/10 inhibition and Alk1 genetic deletion. Mechanistically, endothelial cell late G1 state induced by palbociclib modulates the expression of genes regulating arteriovenous identity, endothelial cell migration, metabolism, and VEGF-A (vascular endothelial growth factor A) and BMP9 signaling that collectively contribute to the prevention of vascular malformations. This study provides new insights into molecular mechanisms leading to HHT by defining how endothelial cell cycle is dysregulated in AVMs because of BMP9/10 and Alk1 signaling deficiencies, and how restoration of endothelial cell cycle control may be used to treat AVMs in patients with HHT.

Neurovascular disease: 2022 update.

In this update we present a series of papers focused on topics that have emerged in vascular disease over the prior year. The first two papers focus on the pathogenesis of vascular malformations, the first on brain arteriovenous malformations, and the second on cerebral cavernous malformations. These disorders can lead to significant brain injuries from intracerebral hemorrhage (if they rupture) or other neurological complications, including seizures. The next set of papers reflects work that has advanced our understanding of how the brain and the immune system "communicate" after brain injury, including stroke (papers 3-6). The first of these shows that T cells are involved in white matter repair after ischemic injury, an effect dependent on microglia, demonstrating the important cross-talk between innate and adaptive immunity. The next two papers focus on B cells, which have been relatively understudied in the context of brain injury. The contribution of antigen-experienced B cells from the meninges and skull bone marrow, rather than blood-derived B cells in neuroinflammation opens up a very novel area of investigation. The possibility that antibody secreting B cells may contribute to vascular dementia will certainly be an active area for future investigations. Similarly, in paper 6, investigators found that CNS-infiltrating myeloid cells can originate from brain borders tissues. These cells have unique transcriptional signatures that are distinct from their blood-derived counterparts, and likely contribute to myeloid cell infiltration from bone-marrow niches in close proximity to the brain. The contribution of microglia, the primary innate immune cell of the brain, to amyloid deposition and propagation is then discussed, followed by work on how perivascular Aβ is potentially cleared along the cerebral vessels in patients with cerebral amyloid angiopathy. The final two papers focus on the contribution of senescent endothelial cells and pericytes. The first used a model of accelerated senescence (Hutchinson-Gilford progeria syndrome; HGPS) and shows the translational potential of an approach to reduce telomere shortening to slow aging. The final paper demonstrates how capillary pericytes contribute to basal blood flow resistance and slow modulation of blood flow throughout the brain. Interestingly, several of the papers identified therapeutic strategies that could be potentially translated into clinical populations.

PIK3CA mutations in vascular malformations.

Recently, it has been discovered that a subset of vascular malformations, of the lymphatic and venous type, are caused by oncogenic mutations in the PIK3CA gene. Now, efforts have been focused in the understanding of the molecular and cellular consequences of these mutations and the opportunities for novel-targeted therapies for these diseases. Here, we review the latest findings in the biology of oncogenic PIK3CA mutations in the pathogenesis of vascular malformations. We focus on the recent development of in-vitro and in-vivo tools for the study of PIK3CA-mutant vascular malformations with special interest in preclinical models for drug testing. Also, we review the latest advances in phosphoinositide 3-kinase (PI3K) inhibitors in the clinic and their repurposing for the treatment of lymphatic malformations and venous malformations. Oncogenic mutations on PIK3CA causing lymphatic malformations and venous malformations are also frequently found in epithelial cancer. Thus, fundamental research done in the cancer field during the past decades might be applied to the understanding of lymphatic malformations and venous malformations. Likewise, repurposing PI3K pathway inhibitors that are currently in cancer clinical trials can be used as a novel strategy for the treatment of these diseases. Here, we also open a debate for the consideration of lymphatic malformations and venous malformations as developmental tumours.

PI3K/mTOR inhibition promotes the regression of experimental vascular malformations driven by PIK3CA-activating mutations

Somatic activating mutations within the PIK3CA gene have been recently detected in sporadic lymphatic and venous malformations, and in vascular malformations (VM) associated to overgrowth syndromes, such as CLOVES and Klippel–Trenaunay syndrome. Although VM are often limited to specific tissue areas and can be well treated, in extended or recurrent lesions novel therapeutic approaches are needed. We generated a mouse model of VM by local expression of PIK3CA-activating mutation in endothelial cells. PIK3CA-driven lesions are characterized by large areas of hemorrhage, hyperplastic vessels, infiltrates of inflammatory cells, and elevated endothelial cell density. Such vascular lesions are ameliorated by administration of dual PI3K/mTOR inhibitor, BEZ235, and mTOR inhibitor, Everolimus. Unexpectedly, the expression of PIK3CA-activating mutations in human endothelial cells results in both increased proliferation rates and senescence. Moreover, active forms of PIK3CA strongly promote the angiogenic sprouting. Treatment with PI3K/mTOR inhibitors restores normal endothelial cell proliferation rate and reduces the amount of senescent cells, whereas treatment with Akt inhibitor is less effective. Our findings reveal that PIK3CA mutations have a key role in the pathogenesis of VM and PIK3CA-driven experimental lesions can be effectively treated by PI3K/mTOR inhibitors.

Circulating Angiogenic Mediators in Patients with Moderate and Severe von Willebrand Disease: A Multicentre Cross-Sectional Study.

Inhibition of von Willebrand factor (VWF) expression in endothelial cells results in enhanced, possible dysfunctional angiogenesis, consistent with observations of severe gastrointestinal bleedings caused by vascular malformations in patients with von Willebrand disease (VWD). VWF is stored in endothelial Weibel-Palade bodies (WPB) with several other mediators of angiogenesis, like angiopoietin-2, osteoprotegerin and galectin-3. Increased release of angiopoietin-2 has been observed in medium of endothelial cells lacking VWF, but data on circulating levels of angiogenic factors in patients with VWD are lacking. The aim of this study was therefore to investigate plasma levels of angiogenic factors in patients with various types of VWD to obtain more insight into the pathogenesis of vascular malformations in these patients. We hypothesized that VWF deficiency leads to increased circulating levels of other WPB components. We therefore measured plasma levels of the WPB components angiopoietin-2, osteoprotegerin and galectin-3 as well as two other angiogenic factors (angiopoietin-1 and vascular endothelial growth factor [VEGF]) that are not stored within WPB. We observed that various angiogenic mediators are significantly different between types of VWD patients. Type 2A VWD patients had higher angiopoietin-1 levels compared with type 2B patients. Patients who have increased VWF clearance had higher angiopoietin-2 levels, whereas patients who have impaired VWF synthesis had higher galectin-3 levels. VEGF levels were negatively associated with VWF levels as type 3 VWD patients had the highest VEGF levels. However, complete VWF deficiency did not lead to increased circulating levels of other WPB components.

The pathobiology of vascular malformations: insights from human and model organism genetics.

Vascular malformations may arise in any of the vascular beds present in the human body. These lesions vary in location, type, and clinical severity of the phenotype. In recent years, the genetic basis of several vascular malformations has been elucidated. This review will consider how the identification of the genetic factors contributing to different vascular malformations, with subsequent functional studies in animal models, has provided a better understanding of these factors that maintain vascular integrity in vascular beds, as well as their role in the pathogenesis of vascular malformations. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Venous malformation associated nerve profiles and pain: An immunohistochemical study

More than 90% of venous malformations (VM) are associated with pain, which is presumed related to phlebolith formation and subsequent nociceptive mediator release. Increasing evidence supports a link between angiogenesis and nerve patterning. Since vascular malformations are aberrations of angiogenesis, it was hypothesised VM pain may be due to differences in nerve profiles associated with these lesions. Immunohistochemical staining was performed on retrospective archival paraffin embedded samples of arteriovenous (AVM; n = 9), capillary (CM; n = 4), lymphatic (LM; n = 29) and VM (n = 14). Antibodies to three nerve markers, neurofilament, S100 and protein gene product 9.5 were employed. Light microscopy was used to assess the density of interstitial nerves and nervi vasorum, and assessments were validated by a second investigator. Significance testing was performed using Mann-Whitney U and Fisher's exact tests. There was no significant difference in nerve profile between VM and AVM or CM. LM and normal control skin each exhibited a lower nerve density compared to VM (p < 0.0075). The presence of nervi vasorum was found to be lower in VM than normal cutaneous controls when immunostained with S100 antibody (p = 0.044). VM-associated pain is unlikely to be due to simple anatomical differences in nerve structure in this condition. As the nerve profile between VM and normal cutaneous control appears to be distinct, further work may elucidate common neurogenic/angiogenic mediators in the pathogenesis of vascular malformations which could prove targets in treating these conditions. In the meantime, current regimes of compression and non-steroidal anti-inflammatory drugs should be continued.

Breast Cancer in Association with Radial Scar/Complex Sclerosing Lesion (rs/csl): Long Term Follow Up and Risk of Subsequent Breast Cancer

Breast Cancer in Association with Radial Scar/Complex Sclerosing Lesion (rs/csl): Long Term Follow Up and Risk of Subsequent Breast Cancer

Active Angiogenesis in an Extensive Arteriovenous Vascular Malformation

Vascular malformations result from the aberrant development of vascular elements during embryogenesis and fetal maturation. Despite apparent endothelial quiescence, some vascular malformations can expand rapidly during adolescence or pregnancy, after a surgical procedure, or in response to trauma. The pathogenesis of vascular malformations is not well clarified, but their formation and progression are closely related to angiogenests, a complicated network that is closely regulated by many angiogenic factors.

Pericytes may have an important role in the pathogenesis of vascular malformations

Vascular malformations are a series of congenital developmental abnormalities. The defects in vascular remodeling may contribute to the formation of these unique entities. Pericytes are the component of microvascular system and play a key role in vascular remodeling. It is logical to propose pericytes may play an important role in the pathogenesis of vascular malformations. Target therapies against pericytes probably bring new sight into vascular malformations treatment.

Malformations artérioveineuses intracrâniennes : aspects anatomo-pathologiques

Arteriovenous malformations (AVM) are congenital abnormalities that consist of tangled masses of tortuous arteries, veins and abnormal connecting channels, that apparently result from the lack of development of the local capillary bed. Because of their propensity to bleed, arteriovenous malformations clinically constitute the most significant group of vascular malformations and the most frequent type in surgical specimens. On histologic study, the lesion is composed of arteries with muscular and elastic laminae, veins dilated by the pressure to which they are exposed because of the shunting and ambiguous vessels with both arterial and venous characteristics called arterialized veins. The pathological blood vessels are separated by brain parenchyma that often shows gliosis and hemosiderin pigmentation. The histologic composition of AVM generally permits confident recognition. The pathogenesis of vascular malformations likely involves the abnormal assembly, differentiation of vascular smooth muscle cells in association with dysmorphic vessel wall. AVM exhibit distinct pattern of expression of molecular markers of differentiation and maturity of VSMC as well as vascular endothelial growth factors and their receptors.