Reduced Mural Cell Coverage and Impaired Vessel Integrity After Angiogenic Stimulation in the Alk1-deficient Brain

• Published in: Arteriosclerosis, thrombosis, and vascular biology Vol. 33; no. 2; pp. 305 - 310
• Main Authors: Chen, Wanqiu, Guo, Yi, Walker, Espen J, Shen, Fanxia, Jun, Kristine, Oh, S Paul, Degos, Vincent, Lawton, Michael T, Tihan, Tarik, Davalos, Dimitrios, Akassoglou, Katerina, Nelson, Jeffrey, Pile-Spellman, John, Su, Hua, Young, William L
• Format: Journal Article
• Language: English
• Published: United States American Heart Association, Inc 01.02.2013
• Subjects: 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
• ISSN: 1079-5642; 1524-4636
• DOI: 10.1161/ATVBAHA.112.300485

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 mice (loxP sites flanking exons 4–6) and wild-type mice were injected with 2×10 PFU adenovious-cre recombinase and 2×10 genome copies of adeno-associated virus-vascular endothelial growth factor to induce focal homozygous Alk1 deletion (in Alk1 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 pixels/mm versus 40±13×10; P=0.001), iron deposition (508±506 pixels/mm versus 6±49; P=0.04), and Iba1 microglia/macrophage infiltration (888±420 Iba1 cells/mm 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 versus 931±115, P<0.001), and reduced platelet-derived growth factor receptor-β expression. 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.