Reduced Mural Cell Coverage and Impaired Vessel Integrity After Angiogenic Stimulation in the Alk1-deficient Brain
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 Alk11f/2f mice (loxP sites flanking exons 4–6) and wild-type mice were injected with 2×107 PFU Ad-Cre and 2×109 genome copies of adeno-associated virus-vascular endothelial growth factor to induce focal homozygous Alk1 deletion (in Alk11f/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 (26±9%, P<0.001).
Conclusion—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.
- activin receptor-like kinase 1
- brain arteriovenous malformation
- iron deposition
- platelet-derived growth factor receptor-β
- Received April 18, 2012.
- Accepted December 3, 2012.
- © 2012 American Heart Association, Inc.