Vascular deficiency of Smad4 causes arteriovenous malformations: a mouse model of Hereditary Hemorrhagic Telangiectasia

Crist, Angela M.; Lee, Amanda R.; Patel, Nehal; Westhoff, Dawn E.; Meadows, Stryder M.

doi:10.1007/s10456-018-9602-0

Cited by 94 publications

(100 citation statements)

References 67 publications

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“…PI3K/Akt/mTOR pathway to control the AVMs. This observation concurs with recent data obtained in Smad4-deficient mice, which indicate that abnormal PI3K/Akt activation in ECs is primarily controlled by blood flow and not VEGFR2 (24,58). An important question relates to the drug dosing used in this study and whether it allows the administered drugs to reach concentrations within the expected therapeutic range.…”

Section: Discussionsupporting

confidence: 92%

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.

show abstract

Section: Discussionsupporting

confidence: 92%

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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“…We further found that, although Siro fully inhibited mTOR overactivation in vivo, its anti-AVM effect was only partial and could be significantly potentiated upon VEGFR2 inhibition by Nin, indicating that VEGFR2 can signal independently of the PI3K-Akt-mTOR pathway to control the AVMs. This observation concurs with recent data obtained in Smad4 deficient mice that indicate that abnormal PI3K-Akt activation in ECs is primary controlled by blood flow and not VEGFR2 (24,58).…”

Section: Discussionsupporting

confidence: 93%

Sirolimus plus nintedanib treats vascular pathology in HHT mouse models

Ruíz

Zhao

Chandakkar

et al. 2019

Preprint

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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 BMP9/10immunoblocked (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".

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“…These are mitochondrial apoptosis, endoplasmic reticulum‐related apoptosis and Fas‐mediated death . Notably, brain tissues contain abundant mitochondria which consistently supply energy to sustain brain function such as neurotransmitters release and neuronal survival . Mitochondrial apoptosis has been reported in the progression of cerebral IRI through a poorly understood mechanism .…”

Section: Introductionmentioning

confidence: 99%

“…9,10 Notably, brain tissues contain abundant mitochondria which consistently supply energy to sustain brain function such as neurotransmitters release and neuronal survival. 11,12 Mitochondrial apoptosis has been reported in the progression of cerebral IRI through a poorly understood mechanism. 13,14 At reperfusion stage, mitochondria produce the majority of ROS that are generated, and the latter alters the mitochondrial membrane potential.…”

Section: Introductionmentioning

confidence: 99%

Resveratrol attenuates cerebral ischaemia reperfusion injury via modulating mitochondrial dynamics homeostasis and activating AMPK‐Mfn1 pathway

Gao

Wang

et al. 2019

Int J Experimental Path

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Summary The pathogenesis of cerebral ischaemia reperfusion injury (IRI) has not been fully described. Accordingly, there is little effective drug available for the treatment of cerebral IRI. The aim of our study was to explore the exact role played by Mfn1‐mediated mitochondrial protection in cerebral IRI and evaluate the beneficial action of resveratrol on reperfused brain. Our study demonstrated that hypoxia‐reoxygenation (HR) injury caused N2a cell apoptosis and this process was highly affected by mitochondrial dysfunction. Decreased mitochondrial membrane potential, increased mitochondrial oxidative stress, and an activated mitochondrial apoptosis pathway were noted in HR‐treated N2a cells. Interestingly, resveratrol treatment could attenuate N2a cell apoptosis via sustaining mitochondrial homeostasis. Further, we found that resveratrol modulated mitochondrial performance via activating the Mfn1‐related mitochondrial protective system. Knockdown of Mfn1 could abolish the beneficial effects of resveratrol on HR‐treated N2a cells. Besides, we also report that resveratrol regulated Mfn1 expression via the AMPK pathway; inhibition of AMPK pathway also neutralized the anti‐apoptotic effect of resveratrol on N2a cells in the setting of cerebral IRI. Taken together our results show that mitochondrial damage is closely associated with the progression of cerebral IRI. In addition we also demonstrate the protective action played by resveratrol on reperfused brain and show that this effect is achieved via activating the AMPK‐Mfn1 pathway.

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Vascular deficiency of Smad4 causes arteriovenous malformations: a mouse model of Hereditary Hemorrhagic Telangiectasia

Cited by 94 publications

References 67 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

Sirolimus plus nintedanib treats vascular pathology in HHT mouse models

Resveratrol attenuates cerebral ischaemia reperfusion injury via modulating mitochondrial dynamics homeostasis and activating AMPK‐Mfn1 pathway

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