Pulmonary Arterial Hypertension and Hereditary Haemorrhagic Telangiectasia

Vorselaars, Veronique M.M.; Hosman, Anna E; Westermann, C. J. J.; Snijder, Repke J.; Mager, Johannes J.; Goumans, Marie–José; Post, Marco C.

doi:10.3390/ijms19103203

Cited by 35 publications

(51 citation statements)

References 86 publications

(114 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…However, the recurring and progressive nature of the disease continues to make HHT a highly debilitating disorder associated with life-threatening sequelae. Several disease-modifying therapies have been proposed in preclinical models, and some of them are currently being investigated in clinical trials (49). Notably, Tac was found to be associated with Smad1/5/8-activating properties in ECs and showed some efficacy in reducing pathology in HHT (32) and PAH (37) models and patients (50-52).…”

Section: Discussionmentioning

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

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionmentioning

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

View full text Add to dashboard Cite

show abstract

“…More cases of HHT and pulmonary hypertension were reported among patients with ACVRL1 mutations than among patients with ENG mutations (5). Previous studies, that did not include genetic information about ACVRL1 mutations, found that HHT and pulmonary hypertension patients had a higher mortality, and died due to cardiac diseases associated with pulmonary hypertension, sepsis, and major bleeding related to HHT (6,14,15).…”

Section: Discussionmentioning

confidence: 99%

“…Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant inherited vascular disease that occurs in approximately 1 in 10,000 people worldwide (1)(2)(3); and 85-95% of cases are caused by pathogenic variants of activin A receptor type II-like 1 (ACVRL1) and endoglin (ENG) (1,4). The ACVRL1 and ENG genes encode members of the transforming growth factor (TGF)-β receptor family, and play important roles in different cellular processes, including proliferation, migration, and apoptosis (5). HHT is characterized by arteriovenous malformation in the lung, liver, and brain, and recurrent epistaxis due to telangiectasia.…”

Section: Introductionmentioning

confidence: 99%

Pulmonary Hypertension and Hereditary Hemorrhagic Telangiectasia Related to an <i>ACVRL1</i> Mutation

et al. 2020

View full text Add to dashboard Cite

Pulmonary hypertension and hereditary hemorrhagic telangiectasia (HHT) have an association mediated by activin A receptor type II-like 1 (ACVRL1) gene pathogenic variants. A 30-year-old woman was previously admitted to a hospital due to lung hemorrhage, and was diagnosed with pulmonary hypertension, but stopped follow-up visits. At 48 years of age, she was admitted to our hospital and was diagnosed with HHT. Genetic testing revealed an ACVRL1 pathogenic variant. After the initiation of pulmonary vasodilator treatment, the patient's mean pulmonary artery pressure started to decrease from 43 mmHg, declining to 37 mmHg when she was 58 years of age. This is the first report describing the 28-year follow-up of an HHT and pulmonary hypertension patient with an ACVRL1 mutation.

show abstract

“…However, the recurring and progressive nature of the disease continues to make HHT a highly debilitating disorder associated with life-threatening sequelae. Several disease-modifying therapies have been proposed in preclinical models and some of them are currently being investigated in clinical trials (49). Notably, Tac was found to be associated with Smad1/5/8 activating properties in ECs and showed some efficacy in reducing pathology in HHT (32) and PAH (37) models and patients (50)(51)(52).…”

Section: Discussionmentioning

confidence: 99%

Sirolimus plus nintedanib treats vascular pathology in HHT mouse models

Ruíz

Zhao

Chandakkar

et al. 2019

Preprint

View full text Add to dashboard Cite

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 BMP9/10immunoblocked (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 ALK1deficient 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 HHT patients. This study was supported by NIH/NHLBI grants R01HL139778 (to PM) and R01HL128525 (to SPO), DOD/CDMRP grant PR161205 (to SPO and PM), a Feinstein Institutes for Medical Research fund (to PM), Leducq foundation (ATTRACT, to SPO), and Barrow Neurological Foundation (to SPO). Conflict of interest:The Feinstein Institutes for Medical Research has filled a U.S. provisional patent application (#62/736,564) entitled "Combined sirolimus and nintedanib therapy for vascular lesions and hereditary hemorrhagic telangiectasia".

show abstract

Pulmonary Arterial Hypertension and Hereditary Haemorrhagic Telangiectasia

Cited by 35 publications

References 86 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

Pulmonary Hypertension and Hereditary Hemorrhagic Telangiectasia Related to an <i>ACVRL1</i> Mutation

Sirolimus plus nintedanib treats vascular pathology in HHT mouse models

Contact Info

Product

Resources

About