Brain arteriovenous malformation modeling, pathogenesis, and novel therapeutic targets

Abstract

Patients harboring brain arteriovenous malformation (bAVM) are at life-threatening risk of rupture and intracranial hemorrhage (ICH). The pathogenesis of bAVM has not been completely understood. Current treatment options are invasive, and ≈ 20 % of patients are not offered interventional therapy because of excessive treatment risk. There are no specific medical therapies to treat bAVMs. The lack of validated animal models has been an obstacle for testing hypotheses of bAVM pathogenesis and testing new therapies. In this review, we summarize bAVM model development and bAVM pathogenesis and potential therapeutic targets that have been identified during model development.

Fig. 1. Novel theories of AVM initiation and progression, and new therapeutic targets

EC: endothelial cell; BMDC: bone marrow-derived cells; sFLT: soluble FMS-related tyrosine kinase 1 (sFLT1), also called VEGF receptor-1

Fig. 2. Development of adult onset brain AVM models

AAV1-VEGF [2×10⁹ viral genome (vg)] is used to stimulate brain focal angiogenesis. Ad-Cre (Ad-Cre/AAV-VEGF/Alk1^f/f model), Pdgfb-icreER (pdgfb-icreER/AAV-VEGF/Alk1^f/f) and Rosa-CreER (Rosa-CreER/AAV-VEGF/Engf) are used to delete Alk1 or Eng in Alk1^f/f or Eng^f/f mice.

Fig. 3. Vessel casting showing AVM in the brain angiogenic region

Large tangled vessels resembling bAVM were detected at the injection site of Ad-Cre and AAV-VEGF in the brain of Alk1-floxed mice (black arrow). Bottom images show the enlarged angiogenic foci of the images at the top. Scale bar = 100µm.

Fig. 4. Adult onset bAVM of Eng^2f/2f;R26CreER mice after TM and VEGF treatment

(A) AVM (squared region) in the brain of Eng^2f/2f;R26CreER mice 8 weeks after intra-brain injection of AAV-VEGF and intraperitoneal injection of TM. (B) Enlarged image of the AVM lesion. Latex-perfused veins are clearly shown (arrows). Scale bars: 1 mm in (A) and 200 µm in (B).

Fig. 5. Developmental onset AVMs in the postnatal brain of Eng^2f/2f;SM22α-Cre mice

(A) Representative images of latex dye casting show the AVM vessels (squared region) in the brain of 5-week-old Eng^2f/2f;SM22α-Cre (B) Enlarged images of dotted boxes shown in (A). Arrows indicate latex-casted veins. Arrow head indicates hemorrhage. Due to the particle size in the latex, the dye enters the vein after intra-left cardiac perfusion only when the A–V shunts are present. Scale bars: 1 mm in (A) and 500 µm in (B).

Fig. 6. Brain AVM in mice with endothelial-Alk1 deletion and focal VEGF stimulation (Alk1^iECKO+VEGF)

AVMs also developed in the intestine, lung and around the ear-tag wound. a: artery: v: vein. Scale bars: 1 mm.