Molecular Controls of Arterial Morphogenesis

Simons, Michael; Eichmann, Anne

doi:10.1161/circresaha.116.302953

Cited by 114 publications

(125 citation statements)

References 150 publications

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“…30,31 Pericytes and smooth muscle cells play important roles in regulating angiogenesis and BBB leakage. 34,[51][52][53] We found that ADAMTS13 deficiency in mice increased the ischemic damage to smooth muscle cells and pericytes, resulting in reduced pericyte and smooth muscle cell coverage on microvessels during the later phase of stroke. These effects were accompanied by reduced expression of the BBB tight junction and basement membrane proteins.…”

Section: Discussionmentioning

confidence: 79%

RETRACTED: ADAMTS13 controls vascular remodeling by modifying VWF reactivity during stroke recovery

Cao

Yang

et al. 2017

Blood

102

100

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Key Points• ADAMTS13 controls key steps of vascular remodeling during stroke recovery.• Recombinant ADAMTS13 enhances ischemic neovascularization and vascular repair.Angiogenic response is essential for ischemic brain repair. The von Willebrand factor (VWF)-cleaving protease disintegrin and metalloprotease with thrombospondin type I motif, member 13 (ADAMTS13) is required for endothelial tube formation in vitro, but there is currently no in vivo evidence supporting a function of ADAMTS13 in angiogenesis. Here we show that mice deficient in ADAMTS13 exhibited reduced neovascularization, brain capillary perfusion, pericyte and smooth muscle cell coverage on microvessels, expression of the tight junction and basement membrane proteins, and accelerated blood-brain barrier (BBB) breakdown and extravascular deposits of serum proteins in the peri-infarct cortex at 14 days after stroke. Deficiency of VWF or anti-VWF antibody treatment significantly increased microvessels, perfused capillary length, and reversed pericyte loss and BBB changes in Adamts13 2/2 mice. Furthermore, we observed that ADAMTS13 deficiency decreased angiopoietin-2 and galectin-3 levels in the isolated brain microvessels, whereas VWF deficiency had the opposite effect. Correlating with this, overexpression of angiopoietin-2 by adenoviruses treatment or administration of recombinant galectin-3 normalized microvascular reductions, pericyte loss, and BBB breakdown in Adamts13 2/2 mice. The vascular changes induced by angiopoietin-2 overexpression and recombinant galectin-3 treatment in Adamts13 2/2 mice were abolished by the vascular endothelial growth factor receptor-2 antagonist SU1498. Importantly, treating wild-type mice with recombinant ADAMTS13 at 7 days after stroke markedly increased neovascularization and vascular repair and improved functional recovery at 14 days. Our results suggest that ADAMTS13 controls key steps of ischemic vascular remodeling and that recombinant ADAMTS13 is a putative therapeutic avenue for promoting stroke recovery. (Blood. 2017;130(1):11-22)

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Section: Discussionmentioning

confidence: 79%

RETRACTED: ADAMTS13 controls vascular remodeling by modifying VWF reactivity during stroke recovery

Cao

Yang

et al. 2017

Blood

102

100

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“…ERK signaling is an important mediator of angiogenesis and arteriogenesis downstream of VEGFR2 activation, and VEGF-B increases ERK1/2 phosphorylation in the heart (10,18). Here were found that DOX treatment significantly reduced ERK1/2 phosphorylation, which was reversed by VEGF-B (Fig.…”

Section: Dox-induced Cardiac Atrophy Is Inhibited By Vegf-bmentioning

confidence: 62%

VEGF-B gene therapy inhibits doxorubicin-induced cardiotoxicity by endothelial protection

Räsänen

Degerman

Nissinen

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

108

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Congestive heart failure is one of the leading causes of disability in long-term survivors of cancer. The anthracycline antibiotic doxorubicin (DOX) is used to treat a variety of cancers, but its utility is limited by its cumulative cardiotoxicity. As advances in cancer treatment have decreased cancer mortality, DOX-induced cardiomyopathy has become an increasing problem. However, the current means to alleviate the cardiotoxicity of DOX are limited. We considered that vascular endothelial growth factor-B (VEGF-B), which promotes coronary arteriogenesis, physiological cardiac hypertrophy, and ischemia resistance, could be an interesting candidate for prevention of DOX-induced cardiotoxicity and congestive heart failure. To study this, we administered an adeno-associated viral vector expressing VEGF-B or control vector to normal and tumor-bearing mice 1 wk before DOX treatment, using doses mimicking the concentrations used in the clinics. VEGF-B treatment completely inhibited the DOX-induced cardiac atrophy and whole-body wasting. VEGF-B also prevented capillary rarefaction in the heart and improved endothelial function in DOX-treated mice. VEGF-B also protected cultured endothelial cells from apoptosis and restored their tube formation. VEGF-B increased left ventricular volume without compromising cardiac function, reduced the expression of genes associated with pathological remodeling, and improved cardiac mitochondrial respiration. Importantly, VEGF-B did not affect serum or tissue concentrations of DOX or augment tumor growth. By inhibiting DOX-induced endothelial damage, VEGF-B could provide a novel therapeutic possibility for the prevention of chemotherapy-associated cardiotoxicity in cancer patients.

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“…These findings raise the interesting possibility that the reactivation of developmental processes controlling bone angiogenesis could be utilized to prevent agerelated or disease-induced bone loss. Likewise, the reactivation of pathways promoting artery formation during development (Herbert and Stainier, 2011;Simons and Eichmann, 2015) might potentially prove useful for the treatment of avascular necrosis, which involves the death of bone tissue due to a lack of local blood supply (Eltzschig and Eckle, 2011;Silvestre et al, 2013), although whether findings in the skeletal system of mice are applicable to humans needs to be investigated. Despite many open questions and caveats, we are presented with the exciting opportunity to investigate the precise role of bone blood vessels and EC subpopulations in a variety of physiological and pathobiological settings, which will undoubtedly enhance our mechanistic understanding of the cellular and molecular processes in the developing, adult, ageing and diseased skeletal system.…”

Section: Future Perspectivesmentioning

confidence: 99%

Blood vessel formation and function in bone

2016

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In addition to their conventional role as a conduit system for gases, nutrients, waste products or cells, blood vessels in the skeletal system play active roles in controlling multiple aspects of bone formation and provide niches for hematopoietic stem cells that reside within the bone marrow. In addition, recent studies have highlighted roles for blood vessels during bone healing. Here, we provide an overview of the architecture of the bone vasculature and discuss how blood vessels form within bone, how their formation is modulated, and how they function during development and fracture repair.

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Molecular Controls of Arterial Morphogenesis

Cited by 114 publications

References 150 publications

RETRACTED: ADAMTS13 controls vascular remodeling by modifying VWF reactivity during stroke recovery

RETRACTED: ADAMTS13 controls vascular remodeling by modifying VWF reactivity during stroke recovery

VEGF-B gene therapy inhibits doxorubicin-induced cardiotoxicity by endothelial protection

Blood vessel formation and function in bone

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