Essential role for TMEM100 in vascular integrity but limited contributions to the pathogenesis of hereditary haemorrhagic telangiectasia

Cardiovasc Res. 2015 Mar 1;105(3):353-60. doi: 10.1093/cvr/cvu260. Epub 2014 Dec 23.


Aims: TMEM100 was previously identified as a downstream target of activin receptor-like kinase 1 (ALK1; ACVRL1) signalling. Mutations on ALK1 cause hereditary haemorrhagic telangiectasia (HHT), a vascular disorder characterized by mucocutaneous telangiectases and visceral arteriovenous malformations (AVMs). The aims of this study are to investigate the in vivo role of TMEM100 at various developmental and adult stages and to determine the extent to which TMEM100 contributed to the development of AVMs as a key downstream effector of ALK1.

Methods and results: Blood vasculature in Tmem100-null embryos and inducible Tmem100-null neonatal and adult mice was examined. We found that TMEM100 deficiency resulted in cardiovascular defects at embryonic stage; dilated vessels, hyperbranching, and increased number of filopodia in the retinal vasculature at neonatal stage; and various vascular abnormalities, including internal haemorrhage, arteriovenous shunts, and weakening of vasculature with abnormal elastin layers at adult stage. However, arteriovenous shunts in adult mutant mice appeared to be underdeveloped without typical tortuosity of vessels associated with AVMs. We uncovered that the expression of genes encoding cell adhesion and extracellular matrix proteins was significantly affected in lungs of adult mutant mice. Especially Mfap4, which is associated with elastin fibre formation, was mostly down-regulated.

Conclusion: These results demonstrate that TMEM100 has essential functions for the maintenance of vascular integrity as well as the formation of blood vessels. Our results also indicate that down-regulation of Tmem100 is not the central mechanism of HHT pathogenesis, but it may contribute to the development of vascular pathology of HHT by weakening vascular integrity.

Keywords: ALK1 (ACVRL1); Hereditary haemorrhagic telangiectasia; MFAP4; TMEM100; Vascular integrity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activin Receptors, Type I / genetics
  • Activin Receptors, Type I / metabolism
  • Activin Receptors, Type II
  • Age Factors
  • Animals
  • Arteriovenous Malformations / embryology
  • Arteriovenous Malformations / genetics
  • Arteriovenous Malformations / metabolism*
  • Arteriovenous Malformations / pathology
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism
  • Disease Models, Animal
  • Elastin / metabolism
  • Extracellular Matrix Proteins / genetics
  • Extracellular Matrix Proteins / metabolism
  • Gene Expression Regulation, Developmental
  • Genotype
  • Gestational Age
  • Glycoproteins / genetics
  • Glycoproteins / metabolism
  • Lung / blood supply*
  • Membrane Proteins / deficiency
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Mice, 129 Strain
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Morphogenesis
  • Phenotype
  • Retinal Vessels / abnormalities
  • Retinal Vessels / metabolism*
  • Retinal Vessels / pathology
  • Signal Transduction
  • Telangiectasia, Hereditary Hemorrhagic / embryology
  • Telangiectasia, Hereditary Hemorrhagic / genetics
  • Telangiectasia, Hereditary Hemorrhagic / metabolism*
  • Telangiectasia, Hereditary Hemorrhagic / pathology


  • Carrier Proteins
  • Extracellular Matrix Proteins
  • Glycoproteins
  • MFAP4 protein, mouse
  • Membrane Proteins
  • Tmem100 protein, mouse
  • Elastin
  • Activin Receptors, Type I
  • Activin Receptors, Type II
  • Acvrl1 protein, mouse