Abstract TMP111: Thalidomide and Lenalidomide Treatment Reduces Microhemorrhage in Brain Arteriovenous Malformation in Mice Through Increasing Mural Cell Coverage

Abstract

Introduction: Brain arteriovenous malformations (bAVMs) have an abnormal vessel wall and are prone to rupture. The mechanism of bAVM rupture is unclear. In Alk1 -deficient mice, bAVM vessels have fewer mural cells. In endoglin-deficient mice, thalidomide increases mural cells in retina AVM vessels. We hypothesize that thalidomide and its less toxic analogue, lenalidomide, improve vessel mural cell coverage and reduce microhemorrhage in Alk1 -deficient bAVM. Methods: Brain AVMs were induced in adult Alk1 2f/2f mice through induction of focal Alk1 gene deletion and angiogenic stimulation. Thalidomide was injected intraperitoneally (i.p.) twice per week for six weeks, starting either 2 weeks after model induction when bAVMs were beginning to develop or 8 weeks after when bAVMs were fully developed. Lenalidomide treatment was started 8 weeks after model induction through i.p. injection daily for six weeks. Results: Thalidomide treatment starting 2 weeks after bAVM induction reduced the number of abnormal vessels and microhemorrhage and increased vascular smooth muscle (vSM)-coverage. Thalidomide also increased the expression of platelet-derived growth factor b (pdgfb) and its receptor (pdgfr beta), indicating that pdgfg/pdgfr beta signaling is one of the mechanisms responsible for the improvement of mural cell coverage. Thalidomide and lenalidomide treatment started at the later time point also improved vSM-coverage and showed a trend toward reduction of microhemorrhage and abnormal vessel count. Conclusions: Thalidomide and lenalidomide stabilize the bAVM vessel wall and reduce microhemorrahge. Further studies are needed to determine whether these agents have a possible therapeutic value for patients.