Interaction Between ALK1 Signaling and Connexin40 in the Development of Arteriovenous Malformations

Gkatzis, Konstantinos; Thalgott, Jérémy H.; Dos-Santos-Luis, Damien; Martín, Sabrina; Lamandé, Noël; Disch, F. J. M.; Snijder, Repke J.; Westermann, C. J. J.; Mager, Johannes J.; Oh, Seh–Hoon; Miquerol, Lucile; Arthur, Helen M.; Mummery, Christine L.; Lebrin, Franck

doi:10.1161/atvbaha.115.306719

Cited by 22 publications

(13 citation statements)

References 43 publications

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“…In several mouse models of disrupted ALK1/Endoglin signaling, wounding has been used to induce AVM formation. 58,71 While wound healing is generally thought of as a neo-angiogenesis model, it also involves a robust inflammatory response, further supporting the role of inflammation in this pathology. In a case report, an HHT patient received an immunosuppressive drug regimen after liver transplantation and experienced a complete resolution of her symptoms.…”

Section: Discussionmentioning

confidence: 99%

Impaired SMAD1/5 Mechanotransduction and Cx37 (Connexin37) Expression Enable Pathological Vessel Enlargement and Shunting

Peacock

Tabibian

Criem

et al. 2020

ATVB

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Impaired ALK1 (activin receptor-like kinase-1)/Endoglin/BMP9 (bone morphogenetic protein 9) signaling predisposes to arteriovenous malformations (AVMs). Activation of SMAD1/5 signaling can be enhanced by shear stress. In the genetic disease hereditary hemorrhagic telangiectasia, which is characterized by arteriovenous malformations, the affected receptors are those involved in the activation of mechanosensitive SMAD1/5 signaling. To elucidate how genetic and mechanical signals interact in arteriovenous malformation formation, we sought to identify targets differentially regulated by BMP9 and shear stress. APPROACH AND RESULTS: We identify Cx37 (Connexin37) as a differentially regulated target of ligand-induced and mechanotransduced SMAD1/5 signaling. We show that stimulation of endothelial cells with BMP9 upregulated Cx37, whereas shear stress inhibited this expression. This signaling was SMAD1/5-dependent, and in the absence of SMAD1/5, there was an inversion of the expression pattern. Ablated SMAD1/5 signaling alone caused arteriovenous malformationlike vascular malformations directly connecting the dorsal aorta to the inlet of the heart. In yolk sacs of mouse embryos with an endothelial-specific compound heterozygosity for SMAD1/5, addition of TNFα (tumor necrosis factor-α), which downregulates Cx37, induced development of these direct connections bypassing the yolk sac capillary bed. In wild-type embryos undergoing vascular remodeling, Cx37 was globally expressed by endothelial cells but was absent in regions of enlarging vessels. TNFα and endothelial-specific compound heterozygosity for SMAD1/5 caused ectopic regions lacking Cx37 expression, which correlated to areas of vascular malformations. Mechanistically, loss of Cx37 impairs correct directional migration under flow conditions. CONCLUSIONS: Our data demonstrate that Cx37 expression is differentially regulated by shear stress and SMAD1/5 signaling, and that reduced Cx37 expression is permissive for capillary enlargement into shunts.

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Section: Discussionmentioning

confidence: 99%

Impaired SMAD1/5 Mechanotransduction and Cx37 (Connexin37) Expression Enable Pathological Vessel Enlargement and Shunting

Peacock

Tabibian

Criem

et al. 2020

ATVB

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“…Deletion of this connexin inhibits flow-activated arterial specification in the chick 14 and affects sprouting angiogenesis and mural cell recruitment in the neonatal mouse retina 76 . Furthermore, loss of Cx40 potentiates the appearance of AVMs in Alk1-haploinsufficient animals 77 , suggesting that it may suppress the formation of these vascular defects in wild-type animals, at least in part, by functioning downstream of BMP9/10-Alk1 signaling. Recently, Su et al .…”

Section: Regulators Of Arteriovenous Specificationmentioning

confidence: 99%

Molecular regulation of arteriovenous endothelial cell specification

Fang

Hirschi

2019

F1000Res

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The systemic circulation depends upon a highly organized, hierarchal blood vascular network that requires the successful specification of arterial and venous endothelial cells during development. This process is driven by a cascade of signaling events (including Hedgehog, vascular endothelial growth factor (VEGF), Notch, connexin (Cx), transforming growth factor-beta (TGF- β), and COUP transcription factor 2 (COUP-TFII)) to influence endothelial cell cycle status and expression of arterial or venous genes and is further regulated by hemodynamic flow. Failure of endothelial cells to properly undergo arteriovenous specification may contribute to vascular malformation and dysfunction, such as in hereditary hemorrhagic telangiectasia (HHT) and capillary malformation-arteriovenous malformation (CM-AVM) where abnormal vessel structures, such as large shunts lacking clear arteriovenous identity and function, form and compromise peripheral blood flow. This review provides an overview of recent findings in the field of arteriovenous specification and highlights key regulators of this process.

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“…While, in fact, RASA1 mutations can cause HHT phenotype, making it part of the CM-AVM syndrome spectrum, current research indicates several other genes involved in HHT development and progress [47,51]. So far, the reported genes include ENG, ACVRL1, GDF2 and SMAD4 [24,47,51,[53][54][55][56][57][58]. Interestingly, all these genes are members of the same signaling pathway (TGF-β) and apparently, various alterations in this pathway may lead to different variants of the disease ( Figure 2) [54].…”

Section: Hereditary Hemorrhagic Telangiectasiamentioning

confidence: 99%

Genetic syndromes with vascular malformations – update on molecular background and diagnostics

et al. 2021

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Vascular malformations are present in a great variety of congenital syndromes, either as the predominant or additional feature. They pose a major challenge to the clinician: due to significant phenotype overlap, a precise diagnosis is often difficult to obtain, some of the malformations carry a risk of life threatening complications and, for many entities, treatment is not well established. To facilitate their recognition and aid in differentiation, we present a selection of notable congenital disorders of vascular system development, distinguishing between the heritable germinal and sporadic somatic mutations as their causes. Clinical features, genetic background and comprehensible description of molecular mechanisms is provided for each entity.

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Interaction Between ALK1 Signaling and Connexin40 in the Development of Arteriovenous Malformations

Cited by 22 publications

References 43 publications

Impaired SMAD1/5 Mechanotransduction and Cx37 (Connexin37) Expression Enable Pathological Vessel Enlargement and Shunting

Impaired SMAD1/5 Mechanotransduction and Cx37 (Connexin37) Expression Enable Pathological Vessel Enlargement and Shunting

Molecular regulation of arteriovenous endothelial cell specification

Genetic syndromes with vascular malformations – update on molecular background and diagnostics

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