Role of Angiopoietin-2 in Vascular Physiology and Pathophysiology

Akwii, Racheal G; Sajib, Sanaullah; Zahra, Fatema Tuz; Mikelis, Constantinos M.

doi:10.3390/cells8050471

Cited by 324 publications

(240 citation statements)

References 140 publications

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“…Reductions in ANG2 correlated with clinical responses and suggest that this biomarker may be useful in monitoring disease status. The contribution of ANG2 to the pathophysiology of KLA remains unclear but is suspected given that ANG2 can promote lymphangiogenesis and vascular dysfunction 21‐27 . Further studies in additional KLA patients are needed to validate use of these blood biomarkers in monitoring disease status.…”

Section: Resultsmentioning

confidence: 99%

Kaposiform lymphangiomatosis treated with multimodal therapy improves coagulopathy and reduces blood angiopoietin‐2 levels

Crane

Manfredo

Boscolo

et al. 2020

Pediatric Blood & Cancer

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Kaposiform lymphangiomatosis (KLA) is a rare, life‐threatening congenital lymphatic malformation. Diagnosis is often delayed due to complex indistinct symptoms. Blood angiopoietin‐2 (ANG2) levels are elevated in KLA and may be useful as a biomarker to monitor disease status. We report a 7‐year‐old male child with easy bruising, inguinal swelling, and consumptive coagulopathy, diagnosed with KLA. A multimodal treatment regimen of prednisone, sirolimus, vincristine, and adjunctive zoledronate was used. Plasma ANG2 levels were highly elevated at diagnosis but decreased during treatment. The patient showed significant clinical improvement over a 38‐month period and normalization of ANG2 levels correlated with resolution of the coagulopathy.

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Section: Resultsmentioning

confidence: 99%

Kaposiform lymphangiomatosis treated with multimodal therapy improves coagulopathy and reduces blood angiopoietin‐2 levels

Crane

Manfredo

Boscolo

et al. 2020

Pediatric Blood & Cancer

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“…Ang1 is produced by pericytes, while Ang2 is produced mainly by endothelial cells, and the two have competing effects: Ang1 and PDGF-β have been shown to stabilize endothelial cells, producing mature vessels, while Ang2 has the opposite effect, destabilizing endothelial cells, favoring angiogenesis (77,78). The effects of Ang1 and Ang2 are context-dependent (79,80). VEGF and CXCL12 are produced mainly by tumor cells, and they coordinate endothelial cell migration and angiogenesis (81).…”

Section: Methodsmentioning

confidence: 99%

Combining microenvironment normalization strategies to improve cancer immunotherapy

Mpekris

Voutouri

Baish

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

174

140

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Advances in immunotherapy have revolutionized the treatment of multiple cancers. Unfortunately, tumors usually have impaired blood perfusion, which limits the delivery of therapeutics and cytotoxic immune cells to tumors and also results in hypoxia-a hallmark of the abnormal tumor microenvironment (TME)-that causes immunosuppression. We proposed that normalization of TME using antiangiogenic drugs and/or mechanotherapeutics can overcome these challenges. Recently, immunotherapy with checkpoint blockers was shown to effectively induce vascular normalization in some types of cancer. Although these therapeutic approaches have been used in combination in preclinical and clinical studies, their combined effects on TME are not fully understood. To identify strategies for improved immunotherapy, we have developed a mathematical framework that incorporates complex interactions among various types of cancer cells, immune cells, stroma, angiogenic molecules, and the vasculature. Model predictions were compared with the data from five previously reported experimental studies. We found that low doses of antiangiogenic treatment improve immunotherapy when the two treatments are administered sequentially, but that high doses are less efficacious because of excessive vessel pruning and hypoxia. Stroma normalization can further increase the efficacy of immunotherapy, and the benefit is additive when combined with vascular normalization. We conclude that vessel functionality dictates the efficacy of immunotherapy, and thus increased tumor perfusion should be investigated as a predictive biomarker of response to immunotherapy.immunotherapy | vascular function | normalization | anti-angiogenic therapy | mechanotherapeutics

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“…ANGPT2 has been described as a context-dependent antagonist interfering with angiopoietin-1-induced Tie2 phosphorylation to destroy vascular stability and promote angiogenesis, might confer resistance to antiangiogenic therapy [12], and has emerged as an attractive vascular drug target by blocking the ANGPT2/Tie2 pathway [8,13]. ANGPT2 has been found to be highly expressed in diverse tumor cells and plays an important role in tumor angiogenesis and inflammation [14,15]. Studies have revealed that ANGPT2 is highly expressed in HCC and that the level of ANGPT2 is closely related to the development and prognosis of HCC [16,17].…”

Section: Introductionmentioning

confidence: 99%

Angiopoietin-2 induces angiogenesis via exosomes in human hepatocellular carcinoma

Xie

Wei

et al. 2020

Cell Commun Signal

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Background: Hepatocellular carcinoma (HCC) is the most common primary liver cancer and is a highly vascularized solid tumor. Angiopoietin-2 (ANGPT2) has been described as an attractive target for antiangiogenic therapy. Exosomes are small extracellular vesicles secreted by most cell types and contribute to cell-to-cell communication by delivering functional cargo to recipient cells. The expression of ANGPT2 in tumor-derived exosomes remains unknown. Methods: We detected the ANGPT2 expression in HCC-derived exosomes by immunoblotting, enzyme-linked immunosorbent assay and immunogold labeling, then observed exosomal ANGPT2 internalization and recycling by confocal laser scanning microscopy, co-immunoprecipitation and immunoblotting. We used two HCC cell lines (Hep3B and MHCC97H) to overexpress ANGPT2 by lentivirus infection or knockdown ANGPT2 by the CRISPR/Cas system, then isolated exosomes to coculture with human umbilical vein endothelial cells (HUVECs) and observed the angiogenesis by Matrigel microtubule formation assay, transwell migration assay, wound healing assay, cell counting kit-8 assay, immunoblotting and in vivo tumorigenesis assay. Results: We found that HCC-derived exosomes carried ANGPT2 and delivered it into HUVECs by exosome endocytosis, this delivery led to a notable increase in angiogenesis by a Tie2-independent pathway. Concomitantly, we observed that HCC cell-secreted exosomal ANGPT2 was recycled by recipient HUVECs and might be reused. In addition, the CRISPR-Cas systems to knock down ANGPT2 significantly inhibited the angiogenesis induced by HCC cell-secreted exosomal ANGPT2, and obviously suppressed the epithelial-mesenchymal transition activation in HCC. Conclusions: Taken together, these results reveal a novel pathway of tumor angiogenesis induced by HCC cellsecreted exosomal ANGPT2 that is different from the classic ANGPT2/Tie2 pathway. This way may be a potential therapeutic target for antiangiogenic therapy.

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Role of Angiopoietin-2 in Vascular Physiology and Pathophysiology

Cited by 324 publications

References 140 publications

Kaposiform lymphangiomatosis treated with multimodal therapy improves coagulopathy and reduces blood angiopoietin‐2 levels

Kaposiform lymphangiomatosis treated with multimodal therapy improves coagulopathy and reduces blood angiopoietin‐2 levels

Combining microenvironment normalization strategies to improve cancer immunotherapy

Angiopoietin-2 induces angiogenesis via exosomes in human hepatocellular carcinoma

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