Measuring Cerebral Blood Flow in Moyamoya Angiopathy by Quantitative Magnetic Resonance Angiography Noninvasive Optimal Vessel Analysis.

BACKGROUND: Moyamoya disease causes progressive occlusion of the supraclinoidal internal carotid artery, and middle, anterior, and less frequently the posterior cerebral arteries, carrying the risk of stroke. Blood flow is often partially reconstituted by compensatory moyamoya collaterals and sometimes the posterior circulation. Cerebral revascularization can further augment blood flow. These changes to blood flow within the cerebral vessels, however, are not well characterized. OBJECTIVE: To evaluate blood flow changes resulting from the disease process and revascularization surgery using quantitative magnetic resonance angiography with noninvasive optimal vessel analysis (NOVA). METHODS: We retrospectively analyzed 190 preoperative and postoperative imaging scans in 66 moyamoya patients after revascularization surgery. Images were analyzed for blood flow using NOVA and compared with preoperative angiographic staging and postoperative blood flow. Blood flow rates within superficial temporal artery grafts were compared based on angiographic evidence of patency. RESULTS: Diseased vessels had lower blood flow, correlating with angiographic staging. Flow in posterior cererbal and basilar arteries increased with disease severity, particularly when both the anterior and middle cerebral arteries were occluded. Basilar artery flow and ipsilateral internal carotid artery flow decreased after surgery. Flow rates were different between angiographically robust and poor direct bypass grafts, as well as between robust and patent grafts. CONCLUSION: Preoperative changes in cerebral vessel flow as measured by NOVA correlated with angiographic disease progression. NOVA demonstrated that preoperative augmentation of the posterior circulation decreased after surgery. This report is the first to quantify the shift in collateral supply from the posterior circulation to the bypass graft.

Inhibition of epidermal growth factor receptor tyrosine kinase ameliorates collagen-induced arthritis.

Rheumatoid arthritis (RA) is an autoimmune synovitis characterized by the formation of pannus and the destruction of cartilage and bone in the synovial joints. Although immune cells, which infiltrate the pannus and promote inflammation, play a prominent role in the pathogenesis of RA, other cell types also contribute. Proliferation of synovial fibroblasts, for example, underlies the formation of the pannus, while proliferation of endothelial cells results in neovascularization, which supports the growth of the pannus by supplying it with nutrients and oxygen. The synovial fibroblasts also promote inflammation in the synovium by producing cytokines and chemokines. Finally, osteoclasts cause the destruction of bone. In this study, we show that erlotinib, an inhibitor of the tyrosine kinase epidermal growth factor receptor (EGFR), reduces the severity of established collagen-induced arthritis, a mouse model of RA, and that it does so by targeting synovial fibroblasts, endothelial cells, and osteoclasts. Erlotinib-induced attenuation of autoimmune arthritis was associated with a reduction in number of osteoclasts and blood vessels, and erlotinib inhibited the formation of murine osteoclasts and the proliferation of human endothelial cells in vitro. Erlotinib also inhibited the proliferation and cytokine production of human synovial fibroblasts in vitro. Moreover, EGFR was highly expressed and activated in the synovium of mice with collagen-induced arthritis and patients with RA. Taken together, these findings suggest that EGFR plays a central role in the pathogenesis of RA and that EGFR inhibition may provide benefits in the treatment of RA.

Loss of BRCC3 deubiquitinating enzyme leads to abnormal angiogenesis and is associated with syndromic moyamoya.

Moyamoya is a cerebrovascular angiopathy characterized by a progressive stenosis of the terminal part of the intracranial carotid arteries and the compensatory development of abnormal and fragile collateral vessels, also called moyamoya vessels, leading to ischemic and hemorrhagic stroke. Moyamoya angiopathy can either be the sole manifestation of the disease (moyamoya disease) or be associated with various conditions, including neurofibromatosis, Down syndrome, TAAD (autosomal-dominant thoracic aortic aneurysm), and radiotherapy of head tumors (moyamoya syndromes). Its prevalence is ten times higher in Japan than in Europe, and an estimated 6%-12% of moyamoya disease is familial in Japan. The pathophysiological mechanisms of this condition remain obscure. Here, we report on three unrelated families affected with an X-linked moyamoya syndrome characterized by the association of a moyamoya angiopathy, short stature, and a stereotyped facial dysmorphism. Other symptoms include an hypergonadotropic hypogonadism, hypertension, dilated cardiomyopathy, premature coronary heart disease, premature hair graying, and early bilateral acquired cataract. We show that this syndromic moyamoya is caused by Xq28 deletions removing MTCP1/MTCP1NB and BRCC3. We also show that brcc3 morphant zebrafish display angiogenesis defects that are rescued by endothelium-specific expression of brcc3. Altogether, these data strongly suggest that BRCC3, a deubiquitinating enzyme that is part of the cellular BRCA1 and BRISC complexes, is an important player in angiogenesis and that BRCC3 loss-of-function mutations are associated with moyamoya angiopathy.