Abstract
Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant vascular disorder that leads to abnormal connections between arteries and veins termed arteriovenous malformations (AVM). Mutations in TGFβ pathway members ALK1, ENG and SMAD4 lead to HHT. However, a Smad4 mouse model of HHT does not currently exist. We aimed to create and characterize a Smad4 endothelial cell (EC)-specific, inducible knockout mouse (Smad4f/f;Cdh5-CreERT2) that could be used to study AVM development in HHT. We found that postnatal ablation of Smad4 caused various vascular defects, including the formation of distinct AVMs in the neonate retina. Our analyses demonstrated that increased EC proliferation and size, altered mural cell coverage and distorted artery–vein gene expression are associated with Smad4 deficiency in the vasculature. Furthermore, we show that depletion of Smad4 leads to decreased Vegfr2 expression, and concurrent loss of endothelial Smad4 and Vegfr2 in vivo leads to AVM enlargement. Our work provides a new model in which to study HHT-associated phenotypes and links the TGFβ and VEGF signaling pathways in AVM pathogenesis.
Highlights
Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant vascular disorder that affects 1 in 5000 people worldwide [1, 2]
We showed that endothelial loss of Smad4 recapitulates vascular phenotypes seen in other HHT mouse models, arteriovenous malformations (AVM) formation
Our results demonstrated that increased endothelial cell (EC) proliferation and size, alterations in mural cell coverage and disruption in AV gene expression are associated with Smad4-deficient blood vessels
Summary
Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant vascular disorder that affects 1 in 5000 people worldwide [1, 2]. AVMs, which are direct connections between arteries and veins, are most commonly found in major organs such as the brain, liver or lungs. These lesions present a serious health risk and can lead to decreased quality of life and/or early death due to hemorrhaging, stroke and aneurysms [3, 5,6,7,8]. What little we know about the in vivo role of SMAD4 in the vasculature comes from embryonic studies.
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