Reduced mural cell coverage and impaired vessel integrity after angiogenic stimulation in the Alk1-deficient brain

Arterioscler Thromb Vasc Biol. 2013 Feb;33(2):305-10. doi: 10.1161/ATVBAHA.112.300485. Epub 2012 Dec 13.


Objective: Vessels in brain arteriovenous malformations are prone to rupture. The underlying pathogenesis is not clear. Hereditary hemorrhagic telangiectasia type 2 patients with activin receptor-like kinase 1 (Alk1) mutation have a higher incidence of brain arteriovenous malformation than the general population. We tested the hypothesis that vascular endothelial growth factor impairs vascular integrity in the Alk1-deficient brain through reduction of mural cell coverage.

Methods and results: Adult Alk1(1f/2f) mice (loxP sites flanking exons 4-6) and wild-type mice were injected with 2×10(7) PFU adenovious-cre recombinase and 2×10(9) genome copies of adeno-associated virus-vascular endothelial growth factor to induce focal homozygous Alk1 deletion (in Alk1(1f/2f) mice) and angiogenesis. Brain vessels were analyzed 8 weeks later. Compared with wild-type mice, the Alk1-deficient brain had more fibrin (99±30×10(3) pixels/mm(2) versus 40±13×10(3); P=0.001), iron deposition (508±506 pixels/mm(2) versus 6±49; P=0.04), and Iba1(+) microglia/macrophage infiltration (888±420 Iba1(+) cells/mm(2) versus 240±104 Iba1(+); P=0.001) after vascular endothelial growth factor stimulation. In the angiogenic foci, the Alk1-deficient brain had more α-smooth muscle actin negative vessels (52±9% versus 12±7%, P<0.001), fewer vascular-associated pericytes (503±179/mm(2) versus 931±115, P<0.001), and reduced platelet-derived growth factor receptor-β expression.

Conclusions: Reduction of mural cell coverage in response to vascular endothelial growth factor stimulation is a potential mechanism for the impairment of vessel wall integrity in hereditary hemorrhagic telangiectasia type 2-associated brain arteriovenous malformation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actins / metabolism
  • Activin Receptors, Type I / deficiency*
  • Activin Receptors, Type I / genetics
  • Activin Receptors, Type II
  • Animals
  • Becaplermin
  • Blood Vessels / enzymology*
  • Blood Vessels / pathology
  • Brain / blood supply*
  • Dependovirus / genetics
  • Disease Models, Animal
  • Fibrin / metabolism
  • Gene Transfer Techniques
  • Genetic Vectors
  • Iron / metabolism
  • Macrophages / metabolism
  • Macrophages / pathology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Microglia / metabolism
  • Microglia / pathology
  • Neovascularization, Pathologic*
  • Pericytes / enzymology*
  • Pericytes / pathology
  • Proto-Oncogene Proteins c-sis / metabolism
  • Receptor, Platelet-Derived Growth Factor beta / metabolism
  • Telangiectasia, Hereditary Hemorrhagic / enzymology*
  • Telangiectasia, Hereditary Hemorrhagic / genetics
  • Telangiectasia, Hereditary Hemorrhagic / pathology
  • Vascular Endothelial Growth Factor A / genetics
  • Vascular Endothelial Growth Factor A / metabolism*


  • Actins
  • Proto-Oncogene Proteins c-sis
  • Vascular Endothelial Growth Factor A
  • alpha-smooth muscle actin, mouse
  • Becaplermin
  • Fibrin
  • Iron
  • Receptor, Platelet-Derived Growth Factor beta
  • Activin Receptors, Type I
  • Activin Receptors, Type II
  • Acvrl1 protein, mouse

Supplementary concepts

  • Osler-rendu-weber syndrome 2