Matrix Gla protein limits pulmonary arteriovenous malformations in ALK1 deficiency

Boström, Kristina I.; Guihard, Pierre; Medela, Ana María Blázquez; Yao, Jiayi; Moon, Jeremiah H.; Penton, Ashley; Yao, Yucheng

doi:10.1183/09031936.00114714

Cited by 9 publications

(8 citation statements)

References 15 publications

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“…MGP is normally highly expressed in ECs [20,21], and deletion of the Mgp gene in mice causes a number of vascular abnormalities including AVMs and irregular vessel caliber in the lungs, kidneys and brain, an increased number of glomeruli in the kidneys, and calcification in the elastic arteries [6,15,22,8]. The dysregulation of endothelial differentiation and appearance of stem cell characteristics when MGP is reduced, non-functioning or missing, are likely to form the basis for such vascular abnormalities.…”

Section: Discussionmentioning

confidence: 99%

Matrix Gla protein regulates differentiation of endothelial cells derived from mouse embryonic stem cells

et al. 2015

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Matrix Gla protein (MGP) is an antagonist of bone morphogenetic proteins (BMPs) and expressed in vascular endothelial cells. Lack of MGP causes vascular abnormalities in multiple organs in mice. The objective of this study is to define the role of MGP in early endothelial differentiation. We find that expression of endothelial markers is highly induced in Mgp null organs, which, in wild type, contain high MGP expression. Furthermore, Mgp null embryonic stem cells express higher levels of endothelial markers than wild type controls and an abnormal temporal pattern of expression. We also find that the Mgp-deficient endothelial cells adopt characteristics of mesenchymal stem cells. We conclude that loss of MGP causes dysregulation of early endothelial differentiation.

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Section: Discussionmentioning

confidence: 99%

Matrix Gla protein regulates differentiation of endothelial cells derived from mouse embryonic stem cells

et al. 2015

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“…MGP, a BMP inhibitor, is essential for regulating vascular BMP activity [ 34 , 47 , 66 – 68 ]. Loss of MGP causes arteriovenous malformation in cerebrum, lungs, kidneys and retina in mice, which resemble the mouse model for hereditary haemorrhagic telangiectasia type 2 [ 38 , 67 – 69 ].…”

Section: Discussionmentioning

confidence: 99%

Regulating the cell shift of endothelial cell-like myofibroblasts in pulmonary fibrosis

Zhang

Qiao

et al. 2023

Eur Respir J

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Pulmonary fibrosis is a common and severe fibrotic lung disease with high morbidity and mortality. Recent studies have reported a large number of unwanted myofibroblasts appearing in pulmonary fibrosis, and shown that the sustained activation of myofibroblasts is essential for unremitting interstitial fibrogenesis. However, the origin of these myofibroblasts remains poorly understood. Here, we create new mouse models of pulmonary fibrosis and identify a previously unknown population of endothelial cell (EC)-like myofibroblasts in normal lung tissue. We show that these EC-like myofibroblasts significantly contribute myofibroblasts to pulmonary fibrosis, which is confirmed by single-cell RNA sequencing of human pulmonary fibrosis. Using the transcriptional profiles, we identified a small molecule that redirects the differentiation of EC-like myofibroblasts and reduces pulmonary fibrosis in our mouse models. Our study reveals the mechanistic underpinnings of the differentiation of EC-like myofibroblasts in pulmonary fibrosis and may provide new strategies for therapeutic interventions.

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“…The role of MGP in lung development has been studied by the Boström 11 , 15 – 17 and Rannels 18 , 19 groups. Their data showed; (i) MGP is expressed in the lung near the epithelial tips of distal buds 19 , (ii) over-expression of Mgp inhibits vascular growth in the lung by limiting BMP-4 activity and Vegf expression 11 , 15 , (iii) MGP KO mice exhibit excessive vascular branching 15 and finally, (iv) MGP acts as an inhibitory morphogen, acting antagonistically to BMP-4 in an activator/inhibitor reaction-diffusion dynamic system in lung vascular development 11 .…”

Section: Discussionmentioning

confidence: 99%

The influence of a high fat diet on bone and soft tissue formation in Matrix Gla Protein knockout mice

Lanham

Cagampang

Oreffo

2018

Sci Rep

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Studies suggest bone growth and development are influenced by maternal nutrition, during intrauterine and early postnatal life. This study assessed the role of MGP and a maternal high fat diet on vitamin K-dependent proteins’ gene expression and their impact on bone formation. Knockout (KO) offspring were smaller than wild type (WT) littermates, yet possessed the same volume of intrascapular brown adipose tissue. The total proportion of body fat was reduced, but only in animals on a control diet. Lung air volume was observed to be comparable in both KO and WT animals on the same diet. The degree of aortic calcification was reduced in KO animals maintained on a HF diet. KO females on the high fat diet showed reduced cortical bone volume and thickness in the femur and tibia. Gene expression levels of GGCX and VKOR were reduced in control fed KO animals suggesting a potential link between gene expression levels of MGP, GGCX, and VKOR and total volumes of bone, calcified soft tissue, and iBAT; with implications for modulation of body length and mass. Our results confirm the important role for vitamin K in bone and calcified soft tissue, but now extend this role to include iBAT.

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Matrix Gla protein limits pulmonary arteriovenous malformations in ALK1 deficiency

Cited by 9 publications

References 15 publications

Matrix Gla protein regulates differentiation of endothelial cells derived from mouse embryonic stem cells

Matrix Gla protein regulates differentiation of endothelial cells derived from mouse embryonic stem cells

Regulating the cell shift of endothelial cell-like myofibroblasts in pulmonary fibrosis

The influence of a high fat diet on bone and soft tissue formation in Matrix Gla Protein knockout mice

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