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.

Adult Alk1^1f/2f mice (loxP sites flanking exons 4–6) and wild-type mice were injected with 2×10⁷ PFU adenovious-cre recombinase and 2×10⁹ 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±30×10³ pixels/mm² versus 40±13×10³; P=0.001), iron deposition (508±506 pixels/mm² versus 6±49; P=0.04), and Iba1⁺ microglia/macrophage infiltration (888±420 Iba1⁺ cells/mm² 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/mm² versus 931±115, P<0.001), and reduced platelet-derived growth factor receptor-β expression.

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.