ALK1 Loss Results in Vascular Hyperplasia in Mice and Humans Through PI3K Activation

Alsina-Sanchís, Elisenda; García-Ibáñez, Yaiza; Figueiredo, A.; Riera-Domingo, Carla; Figueras, Agnés; Matías‐Guiu, Xavier; Casanovas, Oriol; Botella, Luisa M.; Pujana, Miquel Àngel; Riera‐Mestre, Antoni; Graupera, Mariona; Viñals, Francesc

doi:10.1161/atvbaha.118.310760

Cited by 85 publications

(125 citation statements)

References 55 publications

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“…PI3K/Akt overactivation is also involved in AVM development in ALK1-deficient (30) and endoglin-deficient (31) mice and in patients with HHT2 (36). Specifically, ribosomal protein S6 (S6) phosphorylation, a downstream effector of mTORC1 and Akt, was reported to be increased in the ECs of AVMs in the Alk1 iΔEC mouse retina and in BMP9-and BMP10-immunoblocked (BMP9/10ib) mice (30), another HHT model.…”

Section: Resultsmentioning

confidence: 99%

Correcting Smad1/5/8, mTOR, and VEGFR2 treats pathology in hereditary hemorrhagic telangiectasia models

Ruíz¹,

Zhao²,

Chandakkar³

et al. 2020

Journal of Clinical Investigation

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Hereditary hemorrhagic telangiectasia (HHT), a genetic bleeding disorder leading to systemic arteriovenous malformations (AVMs), is caused by loss-of-function mutations in the ALK1/ENG/Smad1/5/8 pathway. Evidence suggests that HHT pathogenesis strongly relies on overactivated PI3K/Akt/mTOR and VEGFR2 pathways in endothelial cells (ECs). In the BMP9/10-immunoblocked (BMP9/10ib) neonatal mouse model of HHT, we report here that the mTOR inhibitor, sirolimus, and the receptor tyrosine kinase inhibitor, nintedanib, could synergistically fully block, but also reversed, retinal AVMs to avert retinal bleeding and anemia. Sirolimus plus nintedanib prevented vascular pathology in the oral mucosa, lungs, and liver of the BMP9/10ib mice, as well as significantly reduced gastrointestinal bleeding and anemia in inducible ALK1-deficient adult mice. Mechanistically, in vivo in BMP9/10ib mouse ECs, sirolimus and nintedanib blocked the overactivation of mTOR and VEGFR2, respectively. Furthermore, we found that sirolimus activated ALK2-mediated Smad1/5/8 signaling in primary ECs-including in HHT patient blood outgrowth ECs-and partially rescued Smad1/5/8 activity in vivo in BMP9/10ib mouse ECs. These data demonstrate that the combined correction of endothelial Smad1/5/8, mTOR, and VEGFR2 pathways opposes HHT pathogenesis. Repurposing of sirolimus plus nintedanib might provide therapeutic benefit in patients with HHT.

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Section: Resultsmentioning

confidence: 99%

Correcting Smad1/5/8, mTOR, and VEGFR2 treats pathology in hereditary hemorrhagic telangiectasia models

Ruíz¹,

Zhao²,

Chandakkar³

et al. 2020

Journal of Clinical Investigation

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“…Therefore, other unknown mechanisms should be involved in gender differences. New insights in the underlying mechanisms may help to gain a better understanding of HHT pathophisiology and angiogenesis process, and could help to develop new treatments or drug repositioning [46][47][48][49].…”

Section: Discussionmentioning

confidence: 99%

Gender differences in hereditary hemorrhagic telangiectasia severity

Mora-Luján

Iriarte

Alba

et al. 2020

Orphanet J Rare Dis

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Background: Gender differences in organ involvement and clinical severity have been poorly described in hereditary hemorrhagic telangiectasia (HHT). The aim of this study was to describe differences in the severity of HHT manifestations according to gender. Methods: Severity was measured according to Epistaxis Severity Score (ESS), Simple Clinical Scoring Index for hepatic involvement, a general HHT-score, needing for invasive treatment (pulmonary or brain arteriovenous malformations-AVMs-embolization, liver transplantation or Young's surgery) or the presence of adverse outcomes (severe anemia, emergency department-ED-or hospital admissions and mortality). Results: One hundred forty-two (58.7%) women and 100 (41.3%) men were included with a mean age of 48.9 ± 16.6 and 49 ± 16.5 years, respectively. Women presented hepatic manifestations (7.1% vs 0%) and hepatic involvement (59.8% vs 47%), hepatic AVMs (28.2% vs 13%) and bile duct dilatation (4.9% vs 0%) at abdominal CT, and pulmonary AVMs at thoracic CT (35.2% vs 23%) more often than men. The Simple Clinical Scoring Index was higher in women (3.38 ± 1.2 vs 2.03 ± 1.2), and more men were considered at low risk of harboring clinically significant liver disease than women (61% vs 25.3%). These differences were mantained when considering HHT1 and HHT2 patients separetely. Duodenal telangiectasia were more frequent in men than women (21% vs 9.8%). Invasive treatments were more frequently needed in women (28.2% vs 16%) but men needed attention at the ED more often than women (48% vs 28.2%), with no differences in ESS, HHT-score, anemia hospital admissions or mortality. Conclusions: HHT women showed more severe hepatic involvement than men, also among HHT1 and HHT2 patients. Women had higher prevalence of pulmonary AVMs and needed invasive procedures more frequently, while men needed attention at the ED more often. These data might help physicians to individualize HHT patients follow-up.

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“…Despite no clear effects on mRNA levels, TGFβ treatment clearly induced Furin protein levels in brain EC. Endothelial TGFβ can signal through two different TGFβ type I receptors, ALK5 and ALK1, which either promote angiogenesis or induce vascular quiescence respectively [11,32]. TGFβ signaling through ALK5 activates Smad2 and 3 whilst signaling through ALK1 activates Smad1, 5 and 8 [8,42].…”

Section: Discussionmentioning

confidence: 99%

“…In ECs, canonical binding of TGFβ to ALK5 causes downstream activation and phosphorylation of Smad2 resulting in stimulation of angiogenesis [31], whereas signaling via ALK1 induces phosphorylation of Smad1, 5 and 8 and subsequent endothelial quiescence [32]. Exposure of brain ECs to TGFβ but not hypoxia increased phosphorylated Smad2 levels whereas the opposite effect was observed on phospho-Smad1/5 levels (Supp.…”

Section: Furin Activation Is Dependent On Alk5 Signalingmentioning

confidence: 99%

Furin inhibition prevents hypoxic and TGFβ-mediated blood-brain barrier disruption

Baumann

Huang

Gassmann

et al. 2019

Experimental Cell Research

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Hypoxic blood-brain barrier (BBB) dysfunction is a common feature of CNS diseases however mechanisms underlying barrier disturbance are still largely unknown. This study investigated the role of transforming growth factor (TGF), a cytokine known to induce expression of the proprotein convertase Furin, in hypoxia-mediated barrier compromise.We show that exposure of brain endothelial cells (ECs) to hypoxia (1% O2) rapidly stimulates their migration. Additional exogenous TGF (0.4nM) exposure potentiated this effect and increased Furin expression in a TGF type I receptor activin-like kinase 5 (ALK5)-dependent manner (prevented by 10M SB431542). Furin inhibition prevented hypoxia-induced EC migration and blocked TGF-induced potentiation suggesting existence of a feedback loop. TGF and Furin were also critical for hypoxia-induced BBB dysfunction. TGF treatment aggravated hypoxiainduced BBB permeability but ALK5 or Furin blockade reversed injury-induced permeability changes. Thus during insult Furin compromises endothelial integrity by mediating the effects of TGF. Targeting the Furin or ALK5 pathway may offer novel therapeutic strategies for improving BBB stability and CNS function during disease.

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ALK1 Loss Results in Vascular Hyperplasia in Mice and Humans Through PI3K Activation

Abstract: Overall, our results indicate that the BMP9/ALK1 hub critically mediates vascular quiescence by limiting PI3K signaling and suggest that PI3K inhibitors could be used as novel therapeutic agents to treat hereditary hemorrhagic telangiectasia.

Cited by 85 publications

References 55 publications

Correcting Smad1/5/8, mTOR, and VEGFR2 treats pathology in hereditary hemorrhagic telangiectasia models

Correcting Smad1/5/8, mTOR, and VEGFR2 treats pathology in hereditary hemorrhagic telangiectasia models

Gender differences in hereditary hemorrhagic telangiectasia severity

Furin inhibition prevents hypoxic and TGFβ-mediated blood-brain barrier disruption

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