Search

The number of coronavirus disease 2019 (COVID‐19) cases has been increasing significantly, and the disease has evolved into a global pandemic, posing an unprecedented challenge to the healthcare community. Angiotensin‐converting enzyme 2, the binding and entry receptor of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) in hosts, is also expressed on pulmonary vascular endothelium; thus, pulmonary vasculature is a potential target in COVID‐19. Indeed, pulmonary vascular thickening is observed by early clinical imaging, implying a tropism of SARS‐CoV‐2 for pulmonary vasculature. Recent studies reported that COVID‐19 is associated with vascular endothelial damage and dysfunction along with inflammation, coagulopathy, and microthrombosis; all of these pathologic changes are the hallmarks of pulmonary vascular diseases. Notwithstanding the not fully elucidated effects of COVID‐19 on pulmonary vasculature, the vascular endotheliopathy that occurs after infection is attributed to direct infection and indirect damage mainly caused by renin‐angiotensin‐aldosterone system imbalance, coagulation cascade, oxidative stress, immune dysregulation, and intussusceptive angiogenesis. Degradation of endothelial glycocalyx exposes endothelial cell (EC) surface receptors to the vascular lumen, which renders pulmonary ECs more susceptible to SARS‐CoV‐2 infection. The present article reviews the potential pulmonary vascular pathophysiology and clinical presentations in COVID‐19 to provide a basis for clinicians and scientists, providing insights into the development of therapeutic strategies targeting pulmonary vasculature., SARS‐CoV‐2 infection‐induced pulmonary vascular injury and potential treatments target the pulmonary vascular system.

Angiogenesis supplies oxygen and nutrients to growing tumors. Inhibiting angiogenesis may stop tumor growth, but vascular endothelial growth factor inhibitors have limited effect in most tumors. This limited effect may be explained by an additional, less vascular endothelial growth factor-driven form of angiogenesis known as intussusceptive angiogenesis. The importance of intussusceptive angiogenesis in human tumors is not known. Epifluorescence and confocal microscopy was used to visualize intravascular pillars, the hallmark structure of intussusceptive angiogenesis, in tumors. Human malignant melanoma metastases, patient-derived melanoma xenografts in mice (PDX), and genetically engineered v-raf murine sarcoma viral oncogene homolog B1 (BRAF)-induced, phosphatase and TENsin homolog deleted on chromosome 10 (PTEN)-deficient (BPT) mice (BrafCA/+Ptenf/fTyr-Cre+/0-mice) were analyzed for pillars. Gene expression in human melanoma metastases and PDXs was analyzed by RNA sequencing. Matrix metalloproteinase 9 (MMP9) protein expression and T-cell and macrophage infiltration in tumor sections were determined with multiplex immunostaining. Intravascular pillars were detected in human metastases but rarely in PDXs and not in BPT mice. The expression of MMP9 mRNA was higher in human metastases compared with PDXs. High expression of MMP9 protein as well as infiltration of macrophages and T-cells were detected in proximity to intravascular pillars. MMP inhibition blocked formation of pillars, but not tubes or tip cells, invitro. In conclusion, intussusceptive angiogenesis may contribute to the growth of human melanoma metastases. MMP inhibition blocked pillar formation invitro and should be further investigated as a potential anti-angiogenic drug target in metastatic melanoma.

Introduction: Tumor agiogenesis is generally classified in to two types, namely, sprouting and intussusceptive angiogenesis. The formation of new blood vessels from the already existing is termed as sprouting angiogenesis. Many growth factors including endothelial growth factor (VEGF) contribute the formation of new vessels at the tumor sites. On other hand, the tumor able to split the existing blood vessels, this type is termed as intussuscepted angiogenesis and discovered in human colon adenocarcinoma xenograft. In intussuscepted angiogenesis, an existing blood vessel splits into two new blood vessels by formation of trans vascular pillars. Objective: The present study aimed to analyse the nicrovascular density on breast cancer patients using CD 34 immunostaining method. Results: This mis-regulation may lead to the development of cancers. Histological grading with Grade II were more with 19 (63.3%) cases followed by Grade I with 4 (13.3%) and Grade III with 3 (10%) cases. There was increase in mean vascular density in Grade II when compared with Grade I and Grade III. However no significant correlation was observed statistically with a P value of 0.176. Using different antibodies such as CD34, CD31, Factor VIII and CD105 to microvessels differentiation was highlighted. Conclusion: The results showed that the anti-CD34 monoclonal antibody is more sensitive than the anti- CD31 antibody in calculation of MVD in breast cancer as mentioned in previous studies.

Background: Angiogenesis, involving the formation of new blood vessels from preexisting vessels, caters an important biological phenomenon for the growth and development of bodily structures in the human body. Regulation of angiogenesis in non-pathological conditions takes place through a well-defined balanced angiogenic-switch, which upon exposure to various pathological conditions may get altered. This makes the cells change their normal behavior resulting in uncontrolled division and angiogenesis. Methods: The current review tries to present a brief framework of angiogenesis and tumor progression phenomenon along with the latest therapeutic interventions against VEGFR-2 and its future directions. Results: The tumor angiogenic pathways functioning in diverse mechanisms via sprouting angiogenesis, intussusceptive angiogenesis, vascular co-option, vascular mimicry, and glomeruloid angiogenesis are normally activated by varied angiogenic stimulators and their receptors are interrelated to give rise to specialized signaling pathways. Amongst these receptors, VEGFR-2 is found as one of the key, critical mediators in tumor angiogenesis and is seen as a major therapeutic target for combating angiogenesis. Though a number of anti-angiogenic drugs like Ramucirumab, Sunitinib, Axitinib, Sorafenib, etc. showing good survival rates have been developed and approved by FDA against VEGFR-2, but these have also been found to be associated with serious health effects and adverse reactions. Conclusions: An improved or alternative treatment is needed shortly that has a higher survival rate with the least side effects. Innovative strategies, including personalized medicine, nano-medicine, and cancer immunotherapy have also been outlined as an alternative treatment with a discussion on advancements and improvements required for their implementation methods.

Cirrhosis describes the development of excess fibrous tissue around regenerative nodules in response to chronic liver injury and usually leads to irreversible organ damage and end-stage liver disease. During the development of cirrhosis, the formation of collagenous scar tissue is paralleled by a reorganization and remodeling of the hepatic vascular system. To date, macrovascular remodeling in various cirrhosis models has been examined using three-dimensional (3D) imaging modalities, while microvascular changes have been studied mainly by two-dimensional (2D) light microscopic and electron microscopic imaging. Here, we report on the application of high-resolution 3D synchrotron radiation-based microtomography (SRμCT) for the study of the sinusoidal and capillary blood vessel system in three murine models of advanced parenchymal and biliary hepatic fibrosis. SRμCT facilitates the characterization of microvascular architecture and identifies features of intussusceptive angiogenesis in progressive liver fibrosis in a non-destructive 3D manner.

The interest on the role of angiogenesis in the pathogenesis and progression of human interstitial lung diseases is growing, with conventional sprouting (SA) and non-sprouting intussusceptive angiogenesis (IA) being differently represented in specific pulmonary injury patterns. The role of viruses as key regulators of angiogenesis is known for several years. A significantly enhanced amount of new vessel growth, through a mechanism of IA, has been reported in lungs of patients who died from Covid-19; among the angiogenesis-related genes, fibroblast growth factor 2 (FGF2) was found to be upregulated. These findings are intriguing. FGF2 plays a role in some viral infections: the upregulation is involved in the MERS-CoV-induced strong apoptotic response crucial for its highly lytic replication cycle in lung cells, whereas FGF2 is protective against the acute lung injury induced by H1N1 influenza virus, improving the lung wet-to-dry weight ratio. FGF2 plays a role also in regulating IA, acting on pericytes (crucial for the formation of intraluminal pillars), and endothelium, and FGF2-induced angiogenesis may be promoted by inflammation and hypoxia. IA is a faster and probably more efficient process than SA, able to modulate vascular remodeling through pruning of redundant or inefficient blood vessels. We can speculate that IA might have the function of restoring a functional vascular plexus consequently to extensive endothelialitis and alveolar capillary micro-thrombosis observed in Covid-19. Anti-Vascular endothelial growth factor (anti-VEGF) strategies are currently investigated for treatment of severe and critically ill Covid-19 patients, but also FGF2, and its expression and/or signaling, might represent a promising target.

Pericytes are essential components of capillaries in many tissues and organs, contributing to vessel stability and integrity, with additional contributions to microvascular function still being discovered. We review current and foundational studies identifying pericyte differentiation mechanics and their roles in the earliest stages of vessel formation. Recent advances in pericyte-focused tools and models have illuminated critical aspects of pericyte biology including their roles in vascular development. Pericytes likely collaborate with endothelial cells undergoing vasculogenesis, initiating direct interactions during sprouting and intussusceptive angiogenesis. Pericytes also provide important regulation of vascular growth including mechanisms underlying vessel pruning, rarefaction, and subsequent regrowth. A phenotypic transition likely occurs as pericytes shift from roles in vascular development to supporting vessel maturation, homeostasis, and physiology. We provide a forward-looking perspective on pericyte-focused studies of vascular development and applications aimed at basic and clinically relevant insights into pericyte biology.

A meshwork of intraluminal processes in lymph node (LN) sinuses originates during LN development. Lymph flows through the meshwork, which has an important role in immunology and pathology. However, the formation mechanism of intraluminal processes has not been sufficiently studied. Our objective is to assess whether this mechanism is by intussusception, as occurs in transcapillary pillar formation in blood vessel intussusceptive angiogenesis. For this purpose, LNs with developing intrasinusal processes were used (human foetuses, 13-18GW) for serial histologic sections and immunohistochemical procedures. The studies showed (a) sinuses originating from lymphatic sacs around expanded LN anlagen, (b) intra-sinus structures (lined by anti-podoplanin+, VEGFR3+, Prox-1+, CD31+ lymphatic endothelial cells) with characteristics (in serial sections and 3D images) similar to those considered the hallmarks of intussusceptive angiogenesis, including pillars (≤2.5μm, with a collagen core), interstitial tissue structures (ITSs) or larger pillars (>2.5μm, with a more cellular core) and folds (that form pillars when spanning), and (c) remodelled and fused pillars, ITSs and folds, which formed meshworks, compartmentalizing the sinuses into small intercommunicating spaces (segmentation). In conclusion, intussusception participates in the formation of the meshwork of processes in LN sinuses during LN development. This mechanism is also of interest because it contributes to the general knowledge of intussusceptive lymphangiogenesis (which has received less attention than intussusception in blood vessels), provides a basis for further studies and supports a new role for vessel intussusception (formation of an intraluminal meshwork with known action in fluid filtering, cell interactions and immunology).

This third study of the author is based on findings of the previous studies. The first study showed how Becker et. al. constructed the SARS CoV-2 Spike Protein in 2008, with approaches of reverse genetics, and inserted into the backbone of the SARS CoV from 2006 (1). The second study showed, how the three US research groups, involved in the synthetic production of the SARS CoV-2 spike protein, developed and matured the SARS CoV-2 virus by decades of laboratory experiments on recombinant human-animal coronavirus RNA through targeted RNA manipulation (2). This overview aims to investigate the publications on whether the constructed SARS CoV-2 virus can be transmitted between individuals. Requirements for infection and transmission of a virus are translation and replication of viral genome in the host. The findings show that the public has been deliberately deceived with false statements in publications to create the narrative of a bat-evolved virus that can be transmitted between humans. But in fact, a spike protein antigen RNA, called SARS CoV-2, was constructed that has neither the efficient function of translation or replication. The only function of the antigen is to enter the human cells to manipulate the human genome. The antigen is then activated by recurrent external injections misleadingly called vaccines, in order to initiate the spike protein antigen synthesis with a sensitive RNA Probe. Consequently, the entry of synthetic foreign genes into the human genome activates an alert system through a cascade of exacerbated immune reactions, which initiates a self destruction mechanism that leads to exodus of the individual. This prevents, at the price of human life, alien genetic material from being incorporated into the human genome and passed to next generations., This is the english version of the following study "Kann das SARS CoV-2 ��bertragen werden?" published December 1, 2021. The author declares no conflict of interests., {"references":["1. M.A. Emergence of synthetic recombinant bat-human spike protein in the Wuhan SARS CoV-2. Zenodo 2020.https://doi.org/10.5281/zenodo.4532195.","2. M.A. The Story about the constructed SARS COV-2 Virus - A Review of three Research Groups.2021;https://doi.org/10.5281/zenodo.4570941.","3. Lan T. Phan, Thuong V. Nguyen, Quang C. Luong, Thinh V. Nguyen, Hieu T. Nguyen, Hung Q. Le, Thuc T. Nguyen, Thang M. Cao, Quang D. Pham,Importation and Human-to-Human Transmission of a Novel Coronavirus in Vietnam. N Engl J med 2020; 382 (9).","4. Chaolin Huang, Yeming Wang, Xingwang Li, Lili Ren, Jianping Zhao, Yi Hu, Li Zhang, Guohui Fan, Jiuyang Xu, Xiaoying Gu,Zhenshun Cheng, Ting Yu, Jiaan Xia, Yuan Wei, Wenjuan Wu, Xuelei Xie, Wen Yin, Hui Li, Min Liu, Yan Xiao, Hong Gao, Li Guo, Jungang Xie,Guangfa Wang, Rongmeng Jiang, Zhancheng Gao, Qi Jin, Jianwei Wang, Bin Cao, Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. The Lancet 2020; 395: 497-506","5. World Health Organization. Classifications https://www.who.int/standards/classifications/classification-of-diseases, 2021 [accessed 28.11.2021]","6. Sufang Tian, Yong Xiong, Huan Liu, Li Niu, Jianchun Guo, Meiyan Liao, Shu-Yuan Xiao, Pathological study of the 2019 novel coronavirus disease (COVID-19) through postmortem core biopsies.Modern Pathology 2020; 33:1007–1014.","7. https://www.gatesfoundation.org/How-We-Work/Quick-Links/Grants-Database#q/k=chinese%20academy&page=2, 2021 [accessed 2.3.2021]","8. Puja Mehta, Daniel F McAuley, Michael Brown, Emilie Sanchez, Rachel S Tattersall, Jessica J Manson, HLH Across Speciality Collaboration, UK, COVID-19: consider cytokine storm syndromes and immunosuppression.Lancet 2020;395(10229):1033-1034.","9. Xinjuan Sun, Tianyuan Wang, Dayong Cai , Zhiwei Hu , Jin'an Chen, Hui Liao, Liming Zhid , Hongxia Weie , Zhihong Zhang, Yuying Qiug , Jing Wang, Aiping Wang,Cytokine storm intervention in the early stages of COVID-19 pneumonia. Cytokine and Growth Factor Reviews.2020; 53:38–42.","10. Qiurong Ruan, Kun Yang, Wenxia Wang, Lingyu Jiang and Jianxin Song, Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China. Intensive Care Med. 2020;46(5):846-848.","11. Yasmin A. Malik,Properties of Coronavirus and SARS-CoV-2.Malaysian J Pathol2020;42(1):3-11.","12. Wycliffe E. Wei, Zongbin Li, Calvin J. Chiew,; Sarah E. Yong, ; Matthias P. Toh, ; Vernon J. Lee, Presymptomatic Transmission of SARS-CoV-2 — Singapore, January 23–March 16, 2020.US Department of Health and Human Services/Centers for Disease Control and Prevention 2020;69.","13. Inga-Marie Schaefer, Robert F. Padera, Isaac H. Solomon, Sanjat Kanjilal2, Mark M. Hammer, Jason L. Hornick, Lynette M. Sholl,In situ detection of SARS-CoV-2 in lungs and airways of patients with COVID-19.Modern pathology 2020;33,2104–2114.","14. Francesca Caccuri, Antonella Bugatti , Alberto Zani, Antonella De Palma, Dario Di Silvestre Ekta Manocha, Federica Filippini, Serena Messali, Paola Chiodelli, Giovanni Campisi Simona Fiorentini , Fabio Facchetti, Pierluigi Mauri and Arnaldo Caruso,SARS-CoV-2 Infection Remodels the Phenotype and Promotes Angiogenesis of Primary Human Lung Endothelial Cells.Microorganisms 2021; 9, 1438.","15. Joanne M Willey, Linda Sherwood, Christopher J. Woolverton, Lansing M. Prescott, and Joanne M. Willey. Prescott's microbiology. 2011. New York.McGraw-Hill :from p.744.","16. Sarah S. Elsoukkary, Maria Mostyka, Alicia Dillard, Diana R. Berman, Lucy X. Ma, Amy Chadburn, Rhonda K. Yantiss, Jose Jessurun, Surya V. Seshan, Alain C. Borczuk, Steven P. Salvatore, Autopsy Findings in 32 Patients with COVID-19: A Single-Institution Experience. Pathobiology 2021;88:56-68.","17. Silke Stertz, Mike Reichelt, Martin Spiegel, Thomas Kuri, Luis Martínez-Sobrido,Adolfo García-Sastre, Friedemann Weber, Georg Kochs,The intracellular sites of early replication and budding of SARS-coronavirus.Virology 2007; 361: 304–315.","18. Katharina Schubert , Evangelos D. Karousis, Ahmad Jomaa , Alain Scaiola  , Blanca Echeverria1, Lukas-Adrian Gurzeler , Marc Leibundgut, Volker Thiel , Oliver Mühlemann  and Nenad Ban , SARS-CoV-2 Nsp1 binds the ribosomal mRNA channel to inhibit translation. Nature Structural & Molecular Biology 2020;27:959-966.","19. Yuichiro J. Suzuki, Sofia I. Nikolaienko, Vyacheslav A. Dibrova, Yulia V. Dibrova ,Volodymyr M. Vasylyk, Mykhailo Y. Novikov, Nataliia V. Shults, Sergiy G. Gychka,SARS-CoV-2 spike protein-mediated cell signaling in lung vascular cells.Vascular Pharmacology 2021;137:1537-1891.","20. Michelle M. Becker, Rachel L. Graham, Eric F. Donaldson, Barry Rockx, Amy C. Sims, Timothy Sheahan, Raymond J. Pickles, Davide Corti, Robert E. Johnston , Ralph S. Baric, and Mark R. Denison, Synthetic recombinant bat SARS-like coronavirus is infectious in cultured cells and in mice. PNAS 2008; 105(50): 19944–19949","21. Swapnil B. Kadam,Geetika S. Sukhramani,Pratibha Bishnoi,Anupama A. Pable,Vitthal T. Barvkar,SARS‐CoV‐2, the pandemic coronavirus: Molecular and structural insights. Journal of Basic Microbiology 2021;61:180-202.","22. Yue Li, Xinai Yang, Na Wang, Haiyan Wang, Bin Yin, Xiaoping Yang, Wenqing Jiang,GC usage of SARS-CoV-2 genes might adapt to the environment of human lung expressed genes.Molecular Genetics and Genomics 2020;295:1537–1546.","23. Jacomine Krijnse-Locker, Maria Ericsson, Peter J. M. Rottier, and Gareth Grittiths, Characterization of the Budding Compartment of Mouse Hepatitis Virus: Evidence That Transport from the RER to the Golgi Complex Requires only One Vesicular Transport Step.The Journal of Cell Biology 1994;124:55-70.","24. Lili Kuo and Paul S. Masters, Genetic Evidence for a Structural Interaction between the Carboxy Termini of the Membrane and Nucleocapsid Proteins of Mouse Hepatitis Virus. JOURNAL OF VIROLOGY 2001;76(10): 4987–4999.","25. Makoto Ujike, Cheng Huang, Kazuya Shirato, Shinji Makino and Fumihiro Taguchi,The contribution of the cytoplasmic retrieval signal of severe acute respiratory syndrome coronavirus to intracellular accumulation of S proteins and incorporation of S protein into virus-like particles. Journal of General Virology 2016;97:1853–1864.","26. Yu Chen, Qianyun Liu, Deyin Guo, Emerging coronaviruses: Genome structure, replication, and pathogenesis. J Med Virol. 2020;92:418–423.","27. Amanda Jack, Luke S. Ferro, Michael J. Trnka, Eddie Wehri, Amrut Nadgir, Xammy Nguyenla, Katelyn Costa, Sarah Stanley, Julia Schaletzky, Ahmet Yildiz,SARS-CoV-2 nucleocapsid protein forms condensates with viral genomic RNA.PLOS Biology.https://doi.org/10.1371/journal.pbio.3001425.","28. Meng Yuan, Nicholas C. Wu, Xueyong Zhu , Chang-Chun D. Lee, Ray T. Y. So , Huibin Lv , Chris K. P. Mok, Ian A. Wilson,A highly conserved cryptic epitope in the receptor binding domains of SARS-CoV-2 and SARS-CoV.Science 2020; 368, 630–633.","29. Peng Zhou, Xing-Lou Yang, Zheng-Li Shi, A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature 2020;579,270-273.","30. GISAID.https://www.gisaid.org/about-us/grants-and-donations/;2021 [accessed 28.11.2021]","31. Roujian Lu, Xiang Zhao, Juan Li, Peihua Niu, Bo Yang, Honglong Wu, Wenling Wang, Hao Song, Baoying Huang, Na Zhu, Yuhai Bi, Xuejun Ma, Faxian Zhan, Liang Wang, Tao Hu, Hong Zhou, Zhenhong Hu, Weimin Zhou, Li Zhao, Jing Chen, Yao Meng, Ji Wang, Yang Lin, Jianying Yuan, Zhihao Xie, Jinmin Ma, William J Liu, Dayan Wang, Wenbo Xu, Edward C Holmes, George F Gao, Guizhen Wu¶, Weijun Chen¶, Weifeng Shi¶, Wenjie Tan, Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding. The Lancet 2020;395.","32. Tahir S Pillay,Gene of the month: the 2019-nCoV/SARS-CoV-2 novel coronavirus spike protein.J Clin Pathol 2020;73:366–369.","33. Simon Willaume, Emilie Rass, Paula Fontanilla-Ramirez , Angela Moussa, Paul Wanschoor and Pascale Bertrand, A Link between Replicative Stress, Lamin Proteins,and Inflammation.Genes 2021;12: 552.","34. Maximilian Ackermann, Stijn E. Verleden, Mark Kuehnel, Axel Haverich, Tobias Welte, Florian Laenger, Arno Vanstapel, Christopher Werlein, Helge Stark, Alexandar Tzankov, William W. Li,Vincent W. Li, Steven J. Mentzer and Danny Jonigk,Pulmonary Vascular Endothelialitis, Thrombosis, and Angiogenesis in Covid-19.N Engl J Med 2020; 383:120-128.","35. Ward De Spiegelaere, Christophe Casteleyn,Wim Van den Broeck,Johanna Plendl, Mahtab Bahramsoltani, Paul Simoens, Valentin Djonov, Pieter Cornillie,Intussusceptive Angiogenesis: A Biologically Relevant Form of Angiogenesis.J Vasc Res 2012;49:390–404.","36. Arne Burkhardt, Walter Lang, Werner Bergholz, Pathologie-Konferenz.de-Todesursache nach Covid-19 Impfung.2021 https://www.pathologie-konferenz.de, 2021 [accessed 29.11.2021]","37. Markus Wiedmann, Thor Skattør , Arne Stray-Pedersen, Luis Romundstad,Ellen-Ann Antal, Pål Bache Marthinsen, Ingvild Hausberg Sørvoll,Siw Leiknes Ernstsen, Christian G. Lund, Pål Andre Holme,Tonje Okkenhaug Johansen, Cathrine Brunborg, Anne Hege Aamodt,Nina Haagenrud Schultz, Karolina Skagen and Mona Skjelland,Vaccine Induced Immune Thrombotic Thrombocytopenia Causing a Severe Form of Cerebral Venous Thrombosis With High Fatality Rate: A Case Series.Frontiers in Neurology 2021;12.","38. G. Madureira, R. Soares,The misunderstood link between SARS-CoV-2 and angiogenesis. A narrative review.Pulmonology Journal 2021;8.","39. Carolin Edler, Anke Klein, Ann Sophie Schröder, Jan-Peter Sperhake, Benjamin Ondruschka, Deaths associated with newly launched SARS-CoV-2 vaccination (Comirnaty®). 40. Leg Med (Tokyo) 2021; 51: 101895.","40. Fabio De-Giorgio,Vincenzo M. Grassi,Eva Bergamin,Alessandro Cina,Franca Del Nonno, Daniele Colombo, Roberta Nardacci, Laura Falasca , Celeste Conte, Ernesto d'Aloja, Gianfranco Damiani and Giuseppe Vetrugno, Dying \"from\" or \"with\" COVID-19 during the Pandemic: Medico-Legal Issues According to a Population Perspective.Int. J. Environ. Res. Public Health 2021; 18: 8851.","41. Torsten Hansen, Ulf Titze, Nidhi Su Ann Kulamadayil-Heidenreich,Sabine Glombitz, Johannes Josef Tebbe, Christoph Röcken, Birte Schulz,Michael Weise, Ludwig Wilkens, First case of postmortem study in a patient vaccinated against SARS-CoV-2. International Journal of Infectious Diseases 2021;107: 172–175."]}

Diese dritte Studie baut auf Erkenntnissen der vorherigen Studien auf. In der ersten Studie wurde nachgewiesen, wie Becker et. al. im Jahre 2008 das SARS CoV-2 Spike Protein durch Verfahren des Reverse Genetics hergestellt und in das Rückgrat des SARS CoV aus dem Jahre 2006 eingefügt haben(1). Die zweite Studie zeigte, dass die drei US-Forschungsgruppen, die an der künstlichen Herstellung des SARS CoV-2 Spike Proteins beteiligt waren, durch Jahrzehnte langen Laborexperimenten an rekombinanten Mensch-Tier Coronavirus RNA, das SARS CoV-2 Virus durch gezielte RNA Manipulation entwickelt und ausgereift haben(2). Diese Arbeit hat sich zur Aufgabe gemacht, die wissenschaftlichen Veröffentlichungen auf die Fragestellung zu untersuchen, ob das künstlich erstellte SARS CoV-2 Virus überhaupt zwischen Menschen übertragen werden kann. Die notwendige Voraussetzung zur Infektion und Übertragung einer Viruserkrankung ist die Virusvermehrung durch Transkription und Replikation des viralen Genoms im Wirtskörper. Die Studienlage zeigt, dass die Öffentlichkeit gezielt durch falsche Behauptungen in wissenschaftlichen Publikationen getäuscht wurde, um das Narrativ eines von Fledermäusen abstammenden Virus zu erschaffen, welches zwischen Menschen übertragen werden könnte. Tatsächlich wurde eine künstliche RNA mit einem Spike Protein Antigen, genannt SARS CoV-2, erstellt, welches weder eine effiziente Transkriptions- noch Replikationsfähigkeit hat. Dabei hat das Antigen zur Aufgabe in die menschlichen Zellen einzudringen, um dort Manipulationen am Genom vorzunehmen. Das Antigen wird dann durch externe Injektionen, hierbei irreführend Impfungen genannt, aktiviert, um die Spike Proteinsynthese, die durch rezidivierende Injektionen mit einer Spike Protein sensitiven RNA Probe auszulösen. Die Folgen eines Eindringens künstlich fremden Genmaterials in das menschliche Genom ist die Auslösung von Warnmechanismen, die durch eine Kaskade von exazerbierten Immunreaktionen, eine Art Selbstzerstörungsmechanismus einleitet und zum Exodus führen. Somit wird der Einbau fremden Genmaterials ins menschliche Genom, und die Vererbung an nächste Generationen, auf Kosten menschlichen Lebens, verhindert.

Diese dritte Studie baut auf Erkenntnissen der vorherigen Studien auf. In der ersten Studie wurde nachgewiesen, wie Becker et. al. im Jahre 2008 das SARS CoV-2 Spike Protein durch Verfahren des Reverse Genetics hergestellt und in das R��ckgrat des SARS CoV aus dem Jahre 2006 eingef��gt haben(1). Die zweite Studie zeigte, dass die drei US-Forschungsgruppen, die an der k��nstlichen Herstellung des SARS CoV-2 Spike Proteins beteiligt waren, durch Jahrzehnte langen Laborexperimenten an rekombinanten Mensch-Tier Coronavirus RNA, das SARS CoV-2 Virus durch gezielte RNA Manipulation entwickelt und ausgereift haben(2). Diese Arbeit hat sich zur Aufgabe gemacht, die wissenschaftlichen Ver��ffentlichungen auf die Fragestellung zu untersuchen, ob das k��nstlich erstellte SARS CoV-2 Virus ��berhaupt zwischen Menschen ��bertragen werden kann. Die notwendige Voraussetzung zur Infektion und ��bertragung einer Viruserkrankung ist die Virusvermehrung durch Transkription und Replikation des viralen Genoms im Wirtsk��rper. Die Studienlage zeigt, dass die ��ffentlichkeit gezielt durch falsche Behauptungen in wissenschaftlichen Publikationen get��uscht wurde, um das Narrativ eines von Flederm��usen abstammenden Virus zu erschaffen, welches zwischen Menschen ��bertragen werden k��nnte. Tats��chlich wurde eine k��nstliche RNA mit einem Spike Protein Antigen, genannt SARS CoV-2, erstellt, welches weder eine effiziente Transkriptions- noch Replikationsf��higkeit hat. Dabei hat das Antigen zur Aufgabe in die menschlichen Zellen einzudringen, um dort Manipulationen am Genom vorzunehmen. Das Antigen wird dann durch externe Injektionen, hierbei irref��hrend Impfungen genannt, aktiviert, um die Spike Proteinsynthese, die durch rezidivierende Injektionen mit einer Spike Protein sensitiven RNA Probe auszul��sen. Die Folgen eines Eindringens k��nstlich fremden Genmaterials in das menschliche Genom ist die Ausl��sung von Warnmechanismen, die durch eine Kaskade von exazerbierten Immunreaktionen, eine Art Selbstzerst��rungsmechanismus einleitet und zum Exodus f��hren. Somit wird der Einbau fremden Genmaterials ins menschliche Genom, und die Vererbung an n��chste Generationen, auf Kosten menschlichen Lebens, verhindert., The author declares no conflict of interests., {"references":["1. M.A. Emergence of synthetic recombinant bat-human spike protein in the Wuhan SARS CoV-2. Zenodo 2020.https://doi.org/10.5281/zenodo.4532195.","2. M.A. The Story about the constructed SARS COV-2 Virus - A Review of three Research Groups.2021;https://doi.org/10.5281/zenodo.4570941.","3. Lan T. Phan, Thuong V. Nguyen, Quang C. Luong, Thinh V. Nguyen, Hieu T. Nguyen, Hung Q. Le, Thuc T. Nguyen, Thang M. Cao, Quang D. Pham,Importation and Human-to-Human Transmission of a Novel Coronavirus in Vietnam. N Engl J med 2020; 382 (9).","4. Chaolin Huang, Yeming Wang, Xingwang Li, Lili Ren, Jianping Zhao, Yi Hu, Li Zhang, Guohui Fan, Jiuyang Xu, Xiaoying Gu,Zhenshun Cheng, Ting Yu, Jiaan Xia, Yuan Wei, Wenjuan Wu, Xuelei Xie, Wen Yin, Hui Li, Min Liu, Yan Xiao, Hong Gao, Li Guo, Jungang Xie,Guangfa Wang, Rongmeng Jiang, Zhancheng Gao, Qi Jin, Jianwei Wang, Bin Cao, Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. The Lancet 2020; 395: 497-506.","5. World Health Organization. Classifications https://www.who.int/standards/classifications/classification-of-diseases, 2021 [accessed 28.11.2021]","6. Sufang Tian, Yong Xiong, Huan Liu, Li Niu, Jianchun Guo, Meiyan Liao, Shu-Yuan Xiao, Pathological study of the 2019 novel coronavirus disease (COVID-19) through postmortem core biopsies.Modern Pathology 2020; 33:1007–1014.","7. https://www.gatesfoundation.org/How-We-Work/Quick-Links/Grants-Database#q/k=chinese%20academy&page=2, 2021 [accessed 2.3.2021]","8. Puja Mehta, Daniel F McAuley, Michael Brown, Emilie Sanchez, Rachel S Tattersall, Jessica J Manson, HLH Across Speciality Collaboration, UK, COVID-19: consider cytokine storm syndromes and immunosuppression.Lancet 2020;395(10229):1033-1034.","9. Xinjuan Sun, Tianyuan Wang, Dayong Cai , Zhiwei Hu , Jin'an Chen, Hui Liao, Liming Zhid , Hongxia Weie , Zhihong Zhang, Yuying Qiug , Jing Wang, Aiping Wang,Cytokine storm intervention in the early stages of COVID-19 pneumonia. Cytokine and Growth Factor Reviews.2020; 53:38–42.","10. Qiurong Ruan, Kun Yang, Wenxia Wang, Lingyu Jiang and Jianxin Song, Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China. Intensive Care Med. 2020;46(5):846-848.","11. Yasmin A. Malik,Properties of Coronavirus and SARS-CoV-2.Malaysian J Pathol2020;42(1):3-11.","12. Wycliffe E. Wei, Zongbin Li, Calvin J. Chiew,; Sarah E. Yong, ; Matthias P. Toh, ; Vernon J. Lee, Presymptomatic Transmission of SARS-CoV-2 — Singapore, January 23–March 16, 2020.US Department of Health and Human Services/Centers for Disease Control and Prevention 2020;69.","13. Inga-Marie Schaefer, Robert F. Padera, Isaac H. Solomon, Sanjat Kanjilal2, Mark M. Hammer, Jason L. Hornick, Lynette M. Sholl,In situ detection of SARS-CoV-2 in lungs and airways of patients with COVID-19.Modern pathology 2020;33,2104–2114.","14. Francesca Caccuri, Antonella Bugatti , Alberto Zani, Antonella De Palma, Dario Di Silvestre Ekta Manocha, Federica Filippini, Serena Messali, Paola Chiodelli, Giovanni Campisi Simona Fiorentini , Fabio Facchetti, Pierluigi Mauri and Arnaldo Caruso,SARS-CoV-2 Infection Remodels the Phenotype and Promotes Angiogenesis of Primary Human Lung Endothelial Cells.Microorganisms 2021; 9, 1438.","15. Joanne M Willey, Linda Sherwood, Christopher J. Woolverton, Lansing M. Prescott, and Joanne M. Willey. Prescott's microbiology. 2011. New York.McGraw-Hill :from p.744.","16. Sarah S. Elsoukkary, Maria Mostyka, Alicia Dillard, Diana R. Berman, Lucy X. Ma, Amy Chadburn, Rhonda K. Yantiss, Jose Jessurun, Surya V. Seshan, Alain C. Borczuk, Steven P. Salvatore, Autopsy Findings in 32 Patients with COVID-19: A Single-Institution Experience. Pathobiology 2021;88:56-68.","17. Silke Stertz, Mike Reichelt, Martin Spiegel, Thomas Kuri, Luis Martínez-Sobrido,Adolfo García-Sastre, Friedemann Weber, Georg Kochs,The intracellular sites of early replication and budding of SARS-coronavirus.Virology 2007; 361: 304–315.","18. Katharina Schubert , Evangelos D. Karousis, Ahmad Jomaa , Alain Scaiola  , Blanca Echeverria1, Lukas-Adrian Gurzeler , Marc Leibundgut, Volker Thiel , Oliver Mühlemann  and Nenad Ban , SARS-CoV-2 Nsp1 binds the ribosomal mRNA channel to inhibit translation. Nature Structural & Molecular Biology 2020;27:959-966.","19. Yuichiro J. Suzuki, Sofia I. Nikolaienko, Vyacheslav A. Dibrova, Yulia V. Dibrova ,Volodymyr M. Vasylyk, Mykhailo Y. Novikov, Nataliia V. Shults, Sergiy G. Gychka,SARS-CoV-2 spike protein-mediated cell signaling in lung vascular cells.Vascular Pharmacology 2021;137:1537-1891.","20. Michelle M. Becker, Rachel L. Graham, Eric F. Donaldson, Barry Rockx, Amy C. Sims, Timothy Sheahan, Raymond J. Pickles, Davide Corti, Robert E. Johnston , Ralph S. Baric, and Mark R. Denison, Synthetic recombinant bat SARS-like coronavirus is infectious in cultured cells and in mice. PNAS 2008; 105(50): 19944–19949","21. Swapnil B. Kadam,Geetika S. Sukhramani,Pratibha Bishnoi,Anupama A. Pable,Vitthal T. Barvkar,SARS‐CoV‐2, the pandemic coronavirus: Molecular and structural insights. Journal of Basic Microbiology 2021;61:180-202.","22. Yue Li, Xinai Yang, Na Wang, Haiyan Wang, Bin Yin, Xiaoping Yang, Wenqing Jiang,GC usage of SARS-CoV-2 genes might adapt to the environment of human lung expressed genes.Molecular Genetics and Genomics 2020;295:1537–1546.","23. Jacomine Krijnse-Locker, Maria Ericsson, Peter J. M. Rottier, and Gareth Grittiths, Characterization of the Budding Compartment of Mouse Hepatitis Virus: Evidence That Transport from the RER to the Golgi Complex Requires only One Vesicular Transport Step.The Journal of Cell Biology 1994;124:55-70.","24. Lili Kuo and Paul S. Masters, Genetic Evidence for a Structural Interaction between the Carboxy Termini of the Membrane and Nucleocapsid Proteins of Mouse Hepatitis Virus. JOURNAL OF VIROLOGY 2001;76(10): 4987–4999.","25. Makoto Ujike, Cheng Huang, Kazuya Shirato, Shinji Makino and Fumihiro Taguchi,The contribution of the cytoplasmic retrieval signal of severe acute respiratory syndrome coronavirus to intracellular accumulation of S proteins and incorporation of S protein into virus-like particles. Journal of General Virology 2016;97:1853–1864.","26. Yu Chen, Qianyun Liu, Deyin Guo, Emerging coronaviruses: Genome structure, replication, and pathogenesis. J Med Virol. 2020;92:418–423.","27. Amanda Jack, Luke S. Ferro, Michael J. Trnka, Eddie Wehri, Amrut Nadgir, Xammy Nguyenla, Katelyn Costa, Sarah Stanley, Julia Schaletzky, Ahmet Yildiz,SARS-CoV-2 nucleocapsid protein forms condensates with viral genomic RNA.PLOS Biology.https://doi.org/10.1371/journal.pbio.3001425.","28. Meng Yuan, Nicholas C. Wu, Xueyong Zhu , Chang-Chun D. Lee, Ray T. Y. So , Huibin Lv , Chris K. P. Mok, Ian A. Wilson,A highly conserved cryptic epitope in the receptor binding domains of SARS-CoV-2 and SARS-CoV.Science 2020; 368, 630–633.","29. Peng Zhou, Xing-Lou Yang, Zheng-Li Shi, A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature 2020;579,270-273.","30. GISAID.https://www.gisaid.org/about-us/grants-and-donations/;2021 [accessed 28.11.2021]","31. Roujian Lu, Xiang Zhao, Juan Li, Peihua Niu, Bo Yang, Honglong Wu, Wenling Wang, Hao Song, Baoying Huang, Na Zhu, Yuhai Bi, Xuejun Ma, Faxian Zhan, Liang Wang, Tao Hu, Hong Zhou, Zhenhong Hu, Weimin Zhou, Li Zhao, Jing Chen, Yao Meng, Ji Wang, Yang Lin, Jianying Yuan, Zhihao Xie, Jinmin Ma, William J Liu, Dayan Wang, Wenbo Xu, Edward C Holmes, George F Gao, Guizhen Wu¶, Weijun Chen¶, Weifeng Shi¶, Wenjie Tan, Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding. The Lancet 2020;395.","32. Tahir S Pillay,Gene of the month: the 2019-nCoV/SARS-CoV-2 novel coronavirus spike protein.J Clin Pathol 2020;73:366–369.","33. Simon Willaume, Emilie Rass, Paula Fontanilla-Ramirez , Angela Moussa, Paul Wanschoor and Pascale Bertrand, A Link between Replicative Stress, Lamin Proteins,and Inflammation.Genes 2021;12: 552.","34. Maximilian Ackermann, Stijn E. Verleden, Mark Kuehnel, Axel Haverich, Tobias Welte, Florian Laenger, Arno Vanstapel, Christopher Werlein, Helge Stark, Alexandar Tzankov, William W. Li,Vincent W. Li, Steven J. Mentzer and Danny Jonigk,Pulmonary Vascular Endothelialitis, Thrombosis, and Angiogenesis in Covid-19.N Engl J Med 2020; 383:120-128.","35. Ward De Spiegelaere, Christophe Casteleyn,Wim Van den Broeck,Johanna Plendl, Mahtab Bahramsoltani, Paul Simoens, Valentin Djonov, Pieter Cornillie,Intussusceptive Angiogenesis: A Biologically Relevant Form of Angiogenesis.J Vasc Res 2012;49:390–404.","36. Arne Burkhardt, Walter Lang, Werner Bergholz, Pathologie-Konferenz.de-Todesursache nach Covid-19 Impfung.2021 https://www.pathologie-konferenz.de, 2021 [accessed 29.11.2021]","37. Markus Wiedmann, Thor Skattør , Arne Stray-Pedersen, Luis Romundstad,Ellen-Ann Antal, Pål Bache Marthinsen, Ingvild Hausberg Sørvoll,Siw Leiknes Ernstsen, Christian G. Lund, Pål Andre Holme,Tonje Okkenhaug Johansen, Cathrine Brunborg, Anne Hege Aamodt,Nina Haagenrud Schultz, Karolina Skagen and Mona Skjelland,Vaccine Induced Immune Thrombotic Thrombocytopenia Causing a Severe Form of Cerebral Venous Thrombosis With High Fatality Rate: A Case Series.Frontiers in Neurology 2021;12.","38. G. Madureira, R. Soares,The misunderstood link between SARS-CoV-2 and angiogenesis. A narrative review.Pulmonology Journal 2021;8.","39. Carolin Edler, Anke Klein, Ann Sophie Schröder, Jan-Peter Sperhake, Benjamin Ondruschka, Deaths associated with newly launched SARS-CoV-2 vaccination (Comirnaty®). 40. Leg Med (Tokyo) 2021; 51: 101895.","40. Fabio De-Giorgio,Vincenzo M. Grassi,Eva Bergamin,Alessandro Cina,Franca Del Nonno, Daniele Colombo, Roberta Nardacci, Laura Falasca , Celeste Conte, Ernesto d'Aloja, Gianfranco Damiani and Giuseppe Vetrugno, Dying \"from\" or \"with\" COVID-19 during the Pandemic: Medico-Legal Issues According to a Population Perspective.Int. J. Environ. Res. Public Health 2021; 18: 8851.","41. Torsten Hansen, Ulf Titze, Nidhi Su Ann Kulamadayil-Heidenreich,Sabine Glombitz, Johannes Josef Tebbe, Christoph Röcken, Birte Schulz,Michael Weise, Ludwig Wilkens, First case of postmortem study in a patient vaccinated against SARS-CoV-2. International Journal of Infectious Diseases 2021;107: 172–175."]}

American journal of respiratory and critical care medicine : AJRCCM 205(1), 121-125 (2022). doi:10.1164/rccm.202103-0594IM, Published by American Thoracic Society, New York, NY

The formation of new blood vessels and the establishment of vascular networks are crucial during brain development, in the adult healthy brain, as well as in various diseases of the central nervous system. Here, we describe a step-by-step protocol for our recently developed method that enables hierarchical imaging and computational analysis of vascular networks in postnatal and adult mouse brains. The different stages of the procedure include resin-based vascular corrosion casting, scanning electron microscopy, synchrotron radiation and desktop microcomputed tomography imaging, and computational network analysis. Combining these methods enables detailed visualization and quantification of the 3D brain vasculature. Network features such as vascular volume fraction, branch point density, vessel diameter, length, tortuosity and directionality as well as extravascular distance can be obtained at any developmental stage from the early postnatal to the adult brain. This approach can be used to provide a detailed morphological atlas of the entire mouse brain vasculature at both the postnatal and the adult stage of development. Our protocol allows the characterization of brain vascular networks separately for capillaries and noncapillaries. The entire protocol, from mouse perfusion to vessel network analysis, takes ~10 d. This protocol uses vascular corrosion casting, hierarchical synchrotron radiation microcomputed tomography imaging and computational image analysis to assess the 3D vascular network architecture in the entire postnatal and adult mouse brain.

Coronavirus disease-2019 (COVID-19), the disease caused by severe acute respiratory syndrome-coronavirus-2, has claimed more than 4.4 million lives worldwide (as of 20 August 2021). Severe cases of the disease often result in respiratory distress due to cytokine storm, and mechanical ventilation is required. Although, the lungs are the primary organs affected by the disease, more evidence on damage to the heart, kidney, and liver is emerging. A common link in these connections is the cardiovascular network. Inner lining of the blood vessels, called endothelium, is formed by a single layer of endothelial cells. Several clinical manifestations involving the endothelium have been reported, such as its activation via immunomodulation, endotheliitis, thrombosis, vasoconstriction, and distinct intussusceptive angiogenesis (IA), a unique and rapid process of blood-vessel formation by splitting a vessel into two lumens. In fact, the virus directly infects the endothelium via TMPRSS2 spike glycoprotein priming to facilitate ACE-2-mediated viral entry. Recent studies have indicated a significant increase in remodeling of the pulmonary vascular bed via intussusception in patients with COVID-19. However, the lack of circulatory biomarkers for IA limits its detection in COVID-19 pathogenesis. In this review, we describe the implications of angiogenesis in COVID-19, unique features of the pulmonary vascular bed and its remodeling, and a rapid and non-invasive assessment of IA to overcome the technical limitations in patients with COVID-19.

SARS-CoV-2-associated acute respiratory distress syndrome (ARDS) and acute lung injury are life-threatening manifestations of severe viral infection. The pathogenic mechanisms that lead to respiratory complications, such as endothelialitis, intussusceptive angiogenesis, and vascular leakage remain unclear. In this study, by using an immunofluorescence assay and in situ RNA-hybridization, we demonstrate the capability of SARS-CoV-2 to infect human primary lung microvascular endothelial cells (HL-mECs) in the absence of cytopathic effects and release of infectious particles. Preliminary data point to the role of integrins in SARS-CoV-2 entry into HL-mECs in the absence of detectable ACE2 expression. Following infection, HL-mECs were found to release a plethora of pro-inflammatory and pro-angiogenic molecules, as assessed by microarray analyses. This conditioned microenvironment stimulated HL-mECs to acquire an angiogenic phenotype. Proteome analysis confirmed a remodeling of SARS-CoV-2-infected HL-mECs to inflammatory and angiogenic responses and highlighted the expression of antiviral molecules as annexin A6 and MX1. These results support the hypothesis of a direct role of SARS-CoV-2-infected HL-mECs in sustaining vascular dysfunction during the early phases of infection. The construction of virus-host interactomes will be instrumental to identify potential therapeutic targets for COVID-19 aimed to inhibit HL-mEC-sustained inflammation and angiogenesis upon SARS-CoV-2 infection.

Eribulin is a novel microtubule inhibitor that, similar to other types of microtubule inhibitors, induces apoptosis by inhibiting the mitotic division of cells. Besides this direct effect on tumor cells, previous studies have shown that eribulin has the potential to induce tumor vascular remodeling in several different cancers; however, the mechanisms underlying this phenomenon remain unclear. In the present study, we aimed to elucidate whether eribulin is effective against synovial sarcoma, a relatively rare sarcoma that often affects adolescents and young adults, and to histologically investigate the microstructure of tumor vessels after the administration of eribulin. We found that eribulin exhibits potent antitumor activity against synovial sarcoma in a tumor xenograft model and that tumor vessels frequently have intervascular pillars, a hallmark of intussusceptive angiogenesis (IA), after the administration of eribulin. IA is a distinct form of angiogenesis that is involved in normal developmental processes as well as pathological conditions. Our data indicate that IA is potentially involved in eribulin-induced vascular remodeling and thereby suggest previously unacknowledged role of IA in regulating the tumor vasculature after eribulin administration.

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.