Arteriovenous Malformations—Current Understanding of the Pathogenesis with Implications for Treatment

Schimmel, Katharina; Ali, Khadem; Tan, Serena Y.; Teng, Joyce; M., Huy; Stevenson, David A.; Spiekerkoetter, Edda

doi:10.3390/ijms22169037

Cited by 50 publications

(45 citation statements)

References 124 publications

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“…Abdominopelvic arteriovenous malformation (AVM) is an uncommon vascular lesion, for which the etiology is usually congenital, and the diagnosis and treatment are difficult. The AVM is characterized by abnormal connections between supplying arteries and draining veins ( 1 ). It may begin with an asymptomatic lesion, but often progresses over time and expands secondary to trauma or hormonal change, such as that during puberty or pregnancy ( 2 ).…”

Section: Introductionmentioning

confidence: 99%

Case Report: A Rare Abdominopelvic Arteriovenous Malformation: Originating From Splenic Artery and Draining Into Portal Vein

Wang

et al. 2022

Front. Cardiovasc. Med.

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BackgroundAbdominopelvic arteriovenous malformation is an uncommon congenital vascular lesion, for which the diagnosis and treatment are usually difficult. Though embolization and sclerotherapy are the primary treatment strategies, traditional surgical resection remains a valuable option.Case PresentationHerein, we present a 32-year-old female diagnosed with a massive abdominopelvic arteriovenous malformation that originates from the splenic artery and drains into the portal vein. The vascular lesion was evaluated with multiple imaging modalities and then surgically resected successfully. The patient was discharged post-operatively on day 6 and free of symptoms during the 12-month follow-up.ConclusionTo our knowledge, the presented abdominopelvic arteriovenous malformation is the first to be reported in the literature, with such a rare condition originating from the splenic artery and draining into the portal vein.

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Section: Introductionmentioning

confidence: 99%

Case Report: A Rare Abdominopelvic Arteriovenous Malformation: Originating From Splenic Artery and Draining Into Portal Vein

Wang

et al. 2022

Front. Cardiovasc. Med.

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“…Such continued stimulation increases the risk of hemorrhage and bleeding, deteriorated flow can cause blood steal phenomena, and the circulation of high-flow blood creates a relatively hypoxic environment in the proximal tissues at the AVM site. Patients with AVM often have a high hemorrhage risk and may require several surgeries along with embolization and sclerotherapy [ 2 , 3 , 4 ].…”

Section: Introductionmentioning

confidence: 99%

Hypoxia Promotes Angiogenic Effect in Extracranial Arteriovenous Malformation Endothelial Cells

Lee

Cho

Ryu

et al. 2022

IJMS

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Arteriovenous malformation (AVM) is characterized by high-flow blood vessels connecting arteries and veins without capillaries. This disease shows increased angiogenesis and a pathophysiological hypoxic environment in proximal tissues. Here, we analyzed the effects of hypoxia on angiogenesis in the endothelial cells (ECs) of AVM and normal tissues. ECs from human normal and AVM tissues were evaluated using immunocytochemistry with CD31. In vitro tube formation under hypoxia was tested in both ECs using Matrigel. The relative expression of angiogenesis-related genes was measured using real-time PCR. Under normoxia, CD31 was significantly higher in AVM ECs (79.23 ± 0.65%) than in normal ECs (74.15 ± 0.70%). Similar results were observed under hypoxia in AVM ECs (63.85 ± 1.84%) and normal ECs (60.52 ± 0.51%). In the tube formation test under normoxic and hypoxic conditions, the junction count and total vessel length were significantly greater in AVM ECs than normal ECs. Under both normoxia and hypoxia, the angiogenesis-related gene FSTL1 showed a significantly higher expression in AVM ECs than in normal ECs. Under hypoxia, CSPG4 expression was significantly lower in AVM ECs than in normal ECs. Accordingly, the angiogenic effect was increased in AVM ECs compared with that in normal ECs. These results provide a basic knowledge for an AVM treatment strategy.

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“…Previous in vivo studies showed that any of the three HHT gene mutations could cause vascular malformations since knockout alleles for ENG, ACVRL1, and SMAD4 all result in HHT-like phenotypes in mice [1]. Mechanistically, in addition to the TGFß/BMP pathway, several other pathways, such as VEGF, mTOR, and PI3K/AKT signaling pathways, are associated with AVM formation and HHT pathogenesis [1]. Recently, pharmacologically combined treatment with Sirolimus and Nintedanib has been shown to correct Smad1/5/8 reduction and mTOR and VEGFR2 activation.…”

Section: Introductionmentioning

confidence: 99%

“…Hereditary hemorrhagic telangiectasia (HHT), also known as Rendu-Osler-Weber syndrome, is a complex genetic disease that causes abnormalities of blood vessel formation in the liver, lung, brain, skin, nasal mucosa, and gastrointestinal tract [1]. HHT is a rare disease, affecting approximately 1 in 5000-10000 people worldwide [2].…”

Section: Introductionmentioning

confidence: 99%

“…All three HHT gene products function in SMAD-dependent signaling pathways in which the activated Smad complex enters the cell nucleus and regulates transcriptional programs. Previous in vivo studies showed that any of the three HHT gene mutations could cause vascular malformations since knockout alleles for ENG, ACVRL1, and SMAD4 all result in HHT-like phenotypes in mice [1]. Mechanistically, in addition to the TGFß/BMP pathway, several other pathways, such as VEGF, mTOR, and PI3K/AKT signaling pathways, are associated with AVM formation and HHT pathogenesis [1].…”

Section: Introductionmentioning

confidence: 99%

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Identifying transcriptomic downstream targets of genes commonly mutated in Hereditary Hemorrhagic Telangiectasia

Ali

Liu

Schimmel

et al. 2022

Preprint

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Hereditary Hemorrhagic Telangiectasia (HHT) is an autosomal dominant disease that causes arteriovenous vascular malformations (AVMs) in different organs, including the lung. Three genes, ENG (endoglin), ACVRL1 (ALK1) and SMAD4, all members of the TGF-β/BMPR2 signaling pathway, are responsible for over 85% of all HHT cases. However, how these loss-of-function gene mutations lead to AVMs formation and what common downstream signaling they target is unknown. Here, using a combination of siRNA-mediated gene silencing, whole transcriptomic RNA sequencing, bioinformatic analysis, transcriptomic-based drug discovery, endothelial cells functional assays and VEGF signaling analysis, and ex vivo precision cut lung slice (PCLS) cultures approach, we uncovered common downstream transcriptomic gene signatures of HHT-casing genes and identified promising drug for HHT. We found the commonly used BMPR2-signaling downstream target ID1 is not a common downstream target of all the three HHT genes knockdown in human pulmonary microvascular endothelial cells (PMVECs). We identified novel common downstream targets of all the three HHT-causing genes that were enriched for HHT-related biological process and signaling pathways. Among those downstream genes, LYVE1, GPNMB, and MC5R were strong downstream targets that could serve as a better common downstream target than ID1. Furthermore, using the common downstream upregulated genes (HHT disease signature) following HHT gene knockdown, we identified a small molecule drug, Brivanib, that reversed the HHT disease signature, and inhibited VEGF-induced ERK1/2 phosphorylation, proliferation, and angiogenesis in PMVECs and inhibited some of the upregulated HHT disease genes in PCLS. Our findings suggest that Brivanib could be an emerging new drug for HHT.

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Arteriovenous Malformations—Current Understanding of the Pathogenesis with Implications for Treatment

Cited by 50 publications

References 124 publications

Case Report: A Rare Abdominopelvic Arteriovenous Malformation: Originating From Splenic Artery and Draining Into Portal Vein

Case Report: A Rare Abdominopelvic Arteriovenous Malformation: Originating From Splenic Artery and Draining Into Portal Vein

Hypoxia Promotes Angiogenic Effect in Extracranial Arteriovenous Malformation Endothelial Cells

Identifying transcriptomic downstream targets of genes commonly mutated in Hereditary Hemorrhagic Telangiectasia

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