| First Author | Chen W | Year | 2013 |
| Journal | Arterioscler Thromb Vasc Biol | Volume | 33 |
| Issue | 2 | Pages | 305-10 |
| PubMed ID | 23241407 | Mgi Jnum | J:216904 |
| Mgi Id | MGI:5609921 | Doi | 10.1161/ATVBAHA.112.300485 |
| Citation | Chen W, et al. (2013) Reduced mural cell coverage and impaired vessel integrity after angiogenic stimulation in the Alk1-deficient brain. Arterioscler Thromb Vasc Biol 33(2):305-10 |
| abstractText | 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 2x10(7) PFU adenovious-cre recombinase and 2x10(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+/-30x10(3) pixels/mm(2) versus 40+/-13x10(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 alpha-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-beta 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. |
