Anti-angiogenic therapeutic strategies in hereditary hemorrhagic telangiectasia

Ardelean, Daniela S.; Letarte, Michelle

doi:10.3389/fgene.2015.00035

Cited by 50 publications

(51 citation statements)

References 64 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…An obvious example is that heterozygous mutation of ALK1 or ENG causes HHT characterized by arteriovenous malformations and hypervascularization, which concurs with increased VEGF signaling. Therefore, anti-VEGF therapy can be considered to restore angiogenic-angiostatic balance in HHT disease [37, 38]. …”

Section: Discussionmentioning

confidence: 99%

Metformin inhibits ALK1-mediated angiogenesis via activation of AMPK

et al. 2017

View full text Add to dashboard Cite

Anti-VEGF therapy has been proven to be effective in the treatment of pathological angiogenesis. However, therapy resistance often occurs, leading to development of alternative approaches. The present study examines if AMPK negatively regulates ALK1-mediated signaling events and associated angiogenesis. Thus, we treated human umbilical vein endothelial cells with metformin as well as other pharmacological AMPK activators and showed that activation of AMPK inhibited Smad1/5 phosphorylation and tube formation induced by BMP9. This event was mimicked by expression of the active mutant of AMPKα1 and prevented by the dominant negative AMPKα1. Metformin inhibition of BMP9 signaling is possibly mediated by upregulation of Smurf1, leading to degradation of ALK1. Furthermore, metformin suppressed BMP9-induced angiogenesis in mouse matrigel plug. In addition, laser photocoagulation was employed to evaluate the effect of metformin. The data revealed that metformin significantly reduced choroidal neovascularization to a level comparable to LDN212854, an ALK1 specific inhibitor. In conjunction, metformin diminished expression of ALK1 in endothelium of the lesion area. Collectively, our study for the first time demonstrates that AMPK inhibits ALK1 and associated angiogenesis/neovascularization. This may offer us a new avenue for the treatment of related diseases using clinically used pharmacological AMPK activators like metformin in combination with other strategies to enhance the treatment efficacy or in the case of anti-VEGF resistance.

show abstract

Section: Discussionmentioning

confidence: 99%

Metformin inhibits ALK1-mediated angiogenesis via activation of AMPK

et al. 2017

View full text Add to dashboard Cite

show abstract

“…Its importance in vascular development is shown by loss-of-function mutations in the vascular disorder HHT type 1 (HHT1) (Ardelean and Letarte 2015). BMP-9 and -10 are similarly important in vasculogenesis (Chen et al 2013), and mutations in the BMP-9 prodomain and ALK1 cause similar HHT syndromes (Tillet and Bailly 2014).…”

Section: Specificity and Promiscuity In Gf-receptor Interactionsmentioning

confidence: 99%

Structural Biology and Evolution of the TGF-β Family

Hinck

Mueller

Springer

2016

Cold Spring Harb Perspect Biol

315

360

View full text Add to dashboard Cite

We review the evolution and structure of members of the transforming growth factor β (TGF-β) family, antagonistic or agonistic modulators, and receptors that regulate TGF-β signaling in extracellular environments. The growth factor (GF) domain common to all family members and many of their antagonists evolved from a common cystine knot growth factor (CKGF) domain. The CKGF superfamily comprises six distinct families in primitive metazoans, including the TGF-β and Dan families. Compared with Wnt/Frizzled and Notch/Delta families that also specify body axes, cell fate, tissues, and other families that contain CKGF domains that evolved in parallel, the TGF-β family was the most fruitful in evolution. Complexes between the prodomains and GFs of the TGF-β family suggest a new paradigm for regulating GF release by conversion from closed- to open-arm procomplex conformations. Ternary complexes of the final step in extracellular signaling show how TGF-β GF dimers bind type I and type II receptors on the cell surface, and enable understanding of much of the specificity and promiscuity in extracellular signaling. However, structures suggest that when GFs bind repulsive guidance molecule (RGM) family coreceptors, type I receptors do not bind until reaching an intracellular, membrane-enveloped compartment, blurring the line between extra- and intracellular signaling. Modulator protein structures show how structurally diverse antagonists including follistatins, noggin, and members of the chordin family bind GFs to regulate signaling; complexes with the Dan family remain elusive. Much work is needed to understand how these molecular components assemble to form signaling hubs in extracellular environments in vivo.

show abstract

“…However, recent evidence strongly suggests that the disease is caused by abnormal activation of angiogenesis, a process causing excessive EC proliferation and hypervascularization, which ultimately leads to the development of AVMs21. Indeed, ALK1 and endoglin are predominantly expressed in ECs and BMP9/10 signaling is required for proper vascular development and maintenance, as well as for controlling transcriptional responses critically involved in angiogenesis, such as Notch and Wnt signaling pathways22232425.…”

mentioning

confidence: 99%

A mouse model of hereditary hemorrhagic telangiectasia generated by transmammary-delivered immunoblocking of BMP9 and BMP10

Ruíz

Zhao

Chandakkar

et al. 2016

Sci Rep

View full text Add to dashboard Cite

Hereditary hemorrhagic telangiectasia (HHT) is a potentially life-threatening genetic vascular disorder caused by loss-of-function mutations in the genes encoding activin receptor-like kinase 1 (ALK1), endoglin, Smad4, and bone morphogenetic protein 9 (BMP9). Injections of mouse neonates with BMP9/10 blocking antibodies lead to HHT-like vascular defects in the postnatal retinal angiogenesis model. Mothers and their newborns share the same immunity through the transfer of maternal antibodies during lactation. Here, we investigated whether the transmammary delivery route could improve the ease and consistency of administering anti-BMP9/10 antibodies in the postnatal retinal angiogenesis model. We found that anti-BMP9/10 antibodies, when intraperitoneally injected into lactating dams, are efficiently transferred into the blood circulation of lactationally-exposed neonatal pups. Strikingly, pups receiving anti-BMP9/10 antibodies via lactation displayed consistent and robust vascular pathology in the retina, which included hypervascularization and defects in arteriovenous specification, as well as the presence of multiple and massive arteriovenous malformations. Furthermore, RNA-Seq analyses of neonatal retinas identified an increase in the key pro-angiogenic factor, angiopoietin-2, as the most significant change in gene expression triggered by the transmammary delivery of anti-BMP9/10 antibodies. Transmammary-delivered BMP9/10 immunoblocking in the mouse neonatal retina is therefore a practical, noninvasive, reliable, and robust model of HHT vascular pathology.

show abstract

Anti-angiogenic therapeutic strategies in hereditary hemorrhagic telangiectasia

Cited by 50 publications

References 64 publications

Metformin inhibits ALK1-mediated angiogenesis via activation of AMPK

Metformin inhibits ALK1-mediated angiogenesis via activation of AMPK

Structural Biology and Evolution of the TGF-β Family

A mouse model of hereditary hemorrhagic telangiectasia generated by transmammary-delivered immunoblocking of BMP9 and BMP10

Contact Info

Product

Resources

About