Real-time imaging of de novo arteriovenous malformation in a mouse model of hereditary hemorrhagic telangiectasia.

Arteriovenous malformations (AVMs) are vascular anomalies where arteries and veins are directly connected through a complex, tangled web of abnormal arteries and veins instead of a normal capillary network. AVMs in the brain, lung, and visceral organs, including the liver and gastrointestinal tract, result in considerable morbidity and mortality. AVMs are the underlying cause of three major clinical symptoms of a genetic vascular dysplasia termed hereditary hemorrhagic telangiectasia (HHT), which is characterized by recurrent nosebleeds, mucocutaneous telangiectases, and visceral AVMs and caused by mutations in one of several genes, including activin receptor-like kinase 1 (ALK1). It remains unknown why and how selective blood vessels form AVMs, and there have been technical limitations to observing the initial stages of AVM formation. Here we present in vivo evidence that physiological or environmental factors such as wounds in addition to the genetic ablation are required for Alk1-deficient vessels to develop to AVMs in adult mice. Using the dorsal skinfold window chamber system, we have demonstrated for what we believe to be the first time the entire course of AVM formation in subdermal blood vessels by using intravital bright-field images, hyperspectral imaging, fluorescence recordings of direct arterial flow through the AV shunts, and vascular casting techniques. We believe our data provide novel insights into the pathogenetic mechanisms of HHT and potential therapeutic approaches.

Different responses of cavernous malformations and arteriovenous malformations to radiosurgery.

The vascular structure of cavernous malformations (CMs) and arteriovenous malformations (AVMs) is different and they have differing clinical responses to radiosurgery. The structural differences of irradiated and non-irradiated CMs and AVMs were examined to clarify their differential responses to radiosurgery. CMs showed a greater ratio of intraluminal diameter to vessel wall thickness and a lack of subendothelial fibroblasts, myofibroblasts and smooth muscle cells compared with AVMs. Partial proteinaceous clots (19-22% of lumen) formed in CM sinusoids after radiosurgery but complete vaso-occlusion did not occur for up to 6 years after radiosurgery. In contrast, complete vaso-occlusion (91-98% of lumen) by fibrin thrombi that are permanent clots was observed in AVM vessels. Radiation-induced neuronal loss, neurofibrillary degeneration of neurons and myelin fragmentation were typical in the surrounding brain tissue of the irradiated lesions. The different structure and cellular composition of CMs and AVMs is likely to influence their responses to radiosurgery.

Responses of arteriovenous malformations to radiosurgery: ultrastructural changes.

OBJECTIVE: To examine the ultrastructural changes in arteriovenous malformations (AVMs) after radiosurgery and to explore the possible mechanisms of posttreatment obliteration and hemorrhage. METHODS: Twenty-two specimens, among them three irradiated AVMs (size, 3-6 cm), 15 nonirradiated AVMs, and four normal controls were processed for ultrastructural study immediately after removal. Transmission electron microscopy was used to compare the vasculature of irradiated AVMs with nonirradiated AVMs and normal controls. RESULTS: Thirty-three months postradiosurgery, partial vaso-occlusion (36-74% lumen) occurred by coagulation of cytoplasmic debris and proteinaceous material leaking from the endothelium. Forty-eight months postradiosurgery, heterogeneous thrombus formation (86-96% lumen) with fibrinoid and proteinaceous materials was observed. Sixty-four months postradiosurgery, complete luminal closure (90-100% lumen) by a fibrin thrombus was seen in vessels with diameters up to 5.5 mm including feeding arteries and draining veins. In occluded vessels, there was extensive degeneration of endothelial cells, subendothelial fibroblasts, and myofibroblasts. Neoproliferation and endothelialization of smooth muscle cells with Weibel-Palade bodies was observed in arteries. CONCLUSION: Radiosurgery causes irreversible cellular damage of the vascular wall. Partial vaso-occlusion that increases blood flow in remaining vessels and degenerative changes on the blood-brain barrier may contribute to hemorrhage at early stage postradiosurgery. Radiosurgery stimulates neoproliferating and endothelializing smooth muscle cells in vessel walls, which might lead to narrowing of the vessel lumina. Complete vaso-occlusion achieved 64 months postradiosurgery suggested a minimum follow-up duration of 5 years to determine final outcome of radiosurgery. Histological end point of vaso-occlusion of AVMs takes longer time than neuroimaging endpoint of complete obliteration.