ADAMTS13 and its variants promote angiogenesis via upregulation of VEGF and VEGFR2

Lee, Manfai; Keener, Justin; Xiao, Juan; Zheng, X. Long; Rodgers, George M.

doi:10.1007/s00018-014-1667-3

Cited by 28 publications

(16 citation statements)

References 28 publications

(28 reference statements)

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“…(22, 23) Placenta is an excellent model tissue to study angiogenesis and cell invasion. Incubation of HTR-8/SVNEO cells with 0-8 nM of recombinant full-length ADAMTS13 for 48 hours resulted in significantly increased proliferation of the trophoblastic cell line in a dose-dependent manner (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…In the absence of excessive VEGF, ADAMTS13 promotes angiogenesis by upregulating VEGF and phosphorylation of VEGFR2. (22, 23) In the presence of excessive VEGF, ADAMTS13 appears to inhibit angiogenesis by competing with VEGF for binding to its receptor VEGFR. Our results are consistent with the proangiogenic effect of ADAMTS13 previously found in vitro .…”

Section: Discussionmentioning

confidence: 99%

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Expression of ADAMTS13 in Normal and Abnormal Placentae and Its Potential Role in Angiogenesis and Placenta Development

Feng

et al. 2017

ATVB

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Objective ADAMTS13 is primarily synthesized in liver. The biosynthesis and its physiological role in placenta are not known. Approach and Results We employed real time polymerase chain reaction (PCR), immunohistochemistry, and Western blotting analyses, as well as proteolytic cleavage of FRETS-VWF73 to determine ADAMTS13 expression in placenta and trophoblasts obtained from individuals with normal pregnancy and patients with severe preeclampsia. We also determined the role of ADAMTS13 in extravillous trophoblasts using a 3-(4,5-Dimethylthiazol-2-yl)- 2,5-diphenyltetrazolium bromide (MTT) assay, wound scratch assay, transwell migration assay, tube formation assay, and tissue outgrowth assays. We demonstrated that full-length and proteolytically active ADAMTS13 was expressed in normal human placenta, primarily in the trophoblasts and villous core fetal vessel endothelium during pregnancy. Placental expression of ADAMTS13 mRNA, protein, and proteolytic activity was at the highest levels during the first trimester and significantly reduced at the term of gestation. Additionally, significantly reduced levels of placental ADAMTS13 expression was detected under hypoxic conditions and in patients with preeclampsia. In addition, recombinant ADAMTS13 protease stimulated proliferation, migration, invasion, and network formation of trophoblastic cells in culture. Finally, knockdown of ADAMTS13 expression attenuated the ability of tube formation in HTR-8/SVNEO cells and the extravillous trophoblast outgrowth in placental explants. Conclusions Our results demonstrate for the first time the expression of ADAMTS13 mRNA and protein in normal and abnormal placental tissues and its role in promoting angiogenesis and trophoblastic cell development. The findings support the potential role of the ADAMTS13-von Willebrand factor pathway in normal pregnancy and pathogenesis of preeclampsia.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Expression of ADAMTS13 in Normal and Abnormal Placentae and Its Potential Role in Angiogenesis and Placenta Development

Feng

et al. 2017

ATVB

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“…Furthermore, we observed that treatment of mice with rADAMTS13 induced a significant increase in VEGFR-2 phosphorylation ( Figure 4K), which is consistent with a recent in vitro study. 22 Immunohistochemical quantification indicated 44% and 64% increases in CD13…”

Section: A M T S 1 3 -/ -A D a M T S 1 3 -/ -mentioning

confidence: 99%

“…Indeed, ADAMTS13 was recently reported to increase VEGFR-2 phosphorylation and promote proliferation and migration of human umbilical vein endothelial cells in vitro. 22 However, whether ADAMTS13 plays a role in vascular regeneration in vivo remains elusive.…”

Section: Introductionmentioning

confidence: 99%

ADAMTS13 controls vascular remodeling by modifying VWF reactivity during stroke recovery

Cao

Yang

et al. 2017

Blood

101

100

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Key Points• ADAMTS13 controls key steps of vascular remodeling during stroke recovery.• Recombinant ADAMTS13 enhances ischemic neovascularization and vascular repair.Angiogenic response is essential for ischemic brain repair. The von Willebrand factor (VWF)-cleaving protease disintegrin and metalloprotease with thrombospondin type I motif, member 13 (ADAMTS13) is required for endothelial tube formation in vitro, but there is currently no in vivo evidence supporting a function of ADAMTS13 in angiogenesis. Here we show that mice deficient in ADAMTS13 exhibited reduced neovascularization, brain capillary perfusion, pericyte and smooth muscle cell coverage on microvessels, expression of the tight junction and basement membrane proteins, and accelerated blood-brain barrier (BBB) breakdown and extravascular deposits of serum proteins in the peri-infarct cortex at 14 days after stroke. Deficiency of VWF or anti-VWF antibody treatment significantly increased microvessels, perfused capillary length, and reversed pericyte loss and BBB changes in Adamts13 2/2 mice. Furthermore, we observed that ADAMTS13 deficiency decreased angiopoietin-2 and galectin-3 levels in the isolated brain microvessels, whereas VWF deficiency had the opposite effect. Correlating with this, overexpression of angiopoietin-2 by adenoviruses treatment or administration of recombinant galectin-3 normalized microvascular reductions, pericyte loss, and BBB breakdown in Adamts13 2/2 mice. The vascular changes induced by angiopoietin-2 overexpression and recombinant galectin-3 treatment in Adamts13 2/2 mice were abolished by the vascular endothelial growth factor receptor-2 antagonist SU1498. Importantly, treating wild-type mice with recombinant ADAMTS13 at 7 days after stroke markedly increased neovascularization and vascular repair and improved functional recovery at 14 days. Our results suggest that ADAMTS13 controls key steps of ischemic vascular remodeling and that recombinant ADAMTS13 is a putative therapeutic avenue for promoting stroke recovery. (Blood. 2017;130(1):11-22)

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“…Finally, the association could be explained by pathways responding to ADAMTS13. For example, there is preliminary evidence that ADAMTS13 upregulates vascular endothelial growth factor, a protein involved in angiogenesis that may contribute to the development of type 2 diabetes [35,36]. ADAMTS13 may similarly activate other pathways that lead to the development of type 2 diabetes.…”

Section: Discussionmentioning

confidence: 99%

ADAMTS13 activity as a novel risk factor for incident type 2 diabetes mellitus: a population-based cohort study

et al. 2016

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Aims/hypothesis ADAMTS13 is a protease that breaks down von Willebrand factor (VWF) multimers into smaller, less active particles. VWF has been associated with an increased risk of incident type 2 diabetes mellitus. Here, we determine whether ADAMTS13 activity and VWF antigen are associated with incident diabetes. Methods This study included 5176 participants from the Rotterdam Study, a prospective population-based cohort study. Participants were free of diabetes at baseline and followed up for more than 20 years. Cox proportional hazards models were used to examine the association of ADAMTS13 activity and VWF antigen with incident diabetes. Results ADAMTS13 activity was associated with an increased risk of incident diabetes (HR 1.17 [95% CI 1.08, 1.27]) after adjustment for known risk factors and VWF antigen levels. Although ADAMTS13 activity was positively associated with fasting glucose and insulin, the association with incident diabetes did not change when we adjusted for these covariates. ADAMTS13 activity was also associated with incident prediabetes (defined on the basis of both fasting and non-fasting blood glucose) after adjustment for known risk factors (HR 1.11 [95% CI 1.03, 1.19]), while the VWF antigen level was not. VWF antigen was associated with incident diabetes, but this association was attenuated after adjustment for known risk factors. Conclusions/interpretation ADAMTS13 activity appears to be an independent risk factor for incident prediabetes and type 2 diabetes. As the association between ADAMTS13 and diabetes did not appear to be explained by its cleavage of VWF, ADAMTS13 may have an independent role in the development of diabetes.

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ADAMTS13 and its variants promote angiogenesis via upregulation of VEGF and VEGFR2

Cited by 28 publications

References 28 publications

Expression of ADAMTS13 in Normal and Abnormal Placentae and Its Potential Role in Angiogenesis and Placenta Development

Expression of ADAMTS13 in Normal and Abnormal Placentae and Its Potential Role in Angiogenesis and Placenta Development

ADAMTS13 controls vascular remodeling by modifying VWF reactivity during stroke recovery

ADAMTS13 activity as a novel risk factor for incident type 2 diabetes mellitus: a population-based cohort study

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