Title

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

Document Type

Article

Abstract

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. © 2012 American Heart Association, Inc.

Publication Date

2-1-2013

Publication Title

Arteriosclerosis, Thrombosis, and Vascular Biology

ISSN

10795642

E-ISSN

15244636

Volume

33

Issue

2

First Page

305

Last Page

310

PubMed ID

23241407

Digital Object Identifier (DOI)

10.1161/ATVBAHA.112.300485

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