Vascular endothelial growth factor: a neurovascular target in neurological diseases

Lange, Christian; Storkebaum, Erik; Almodóvar, Carmen Ruiz de; Dewerchin, Mieke; Carmeliet, Peter

doi:10.1038/nrneurol.2016.88

Cited by 265 publications

(278 citation statements)

References 199 publications

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“…Interference with VEGF signaling may contribute to the inhibitory effects of Aβ42 on synaptic transmission [77][78][79]. Indeed, VEGF administration has been investigated as a neuroprotective, proangiogenic therapy in AD [80][81][82]. The present study adds to our understanding of VEGF-VEGFR signaling in AD.…”

Section: Discussionmentioning

confidence: 76%

VEGFR1 and VEGFR2 in Alzheimer’s Disease

Harris

Miners

Allen

et al. 2017

JAD

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Section: Discussionmentioning

confidence: 76%

VEGFR1 and VEGFR2 in Alzheimer’s Disease

Harris

Miners

Allen

et al. 2017

JAD

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“…The activation of the VEGFR2 and Wnt-β-catenin pathways in BECs have been shown to induce angiogenesis and mature vessel morphology in the developing CNS (9)(10)(11)(12). Subsequently, TGF-β/TGF-βR and Ang-1/Tie-2 signaling promote further BBB maturation (6).…”

mentioning

confidence: 99%

CD146 coordinates brain endothelial cell–pericyte communication for blood–brain barrier development

Chen

Luo

Hui

et al. 2017

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

150

140

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The blood-brain barrier (BBB) establishes a protective interface between the central neuronal system and peripheral blood circulation and is crucial for homeostasis of the CNS. BBB formation starts when the endothelial cells (ECs) invade the CNS and pericytes are recruited to the nascent vessels during embryogenesis. Despite the essential function of pericyte-EC interaction during BBB development, the molecular mechanisms coordinating the pericyte-EC behavior and communication remain incompletely understood. Here, we report a single cell receptor, CD146, that presents dynamic expression patterns in the cerebrovasculature at the stages of BBB induction and maturation, coordinates the interplay of ECs and pericytes, and orchestrates BBB development spatiotemporally. In mouse brain, CD146 is first expressed in the cerebrovascular ECs of immature capillaries without pericyte coverage; with increased coverage of pericytes, CD146 could only be detected in pericytes, but not in cerebrovascular ECs. Specific deletion of Cd146 in mice ECs resulted in reduced brain endothelial claudin-5 expression and BBB breakdown. By analyzing mice with specific deletion of Cd146 in pericytes, which have defects in pericyte coverage and BBB integrity, we demonstrate that CD146 functions as a coreceptor of PDGF receptor-β to mediate pericyte recruitment to cerebrovascular ECs. Moreover, we found that the attached pericytes in turn downregulate endothelial CD146 by secreting TGF-β1 to promote further BBB maturation. These results reveal that the dynamic expression of CD146 controls the behavior of ECs and pericytes, thereby coordinating the formation of a mature and stable BBB.lood-brain barrier (BBB) development is a sequential and well-orchestrated process that commences when brain endothelial cells (ECs; BECs) invade the embryonic neuroectoderm from the surrounding vascular plexus and induce BBB properties by establishing paracellular tight junctions (TJs) (1). Endothelial TJs are formed by a complex of transmembrane proteins, including claudins and occludin, as well as cytoplasmic adaptors such as zonula occludens protein 1 (ZO-1), thus creating a highresistance paracellular barrier to molecules and ions (2). Compelling evidence shows that claudin-5 plays a key role in the induction of BBB properties, and specific loss of claudin-5 in mice results in a more leaky BBB (3-5). Following the establishment of the TJs, the BECs of nascent vessels recruit pericytes to the endothelial walls, which improve the barrier function of BECs by stabilizing TJs and decreasing transcytosis, and are crucial for maturation of the BBB (6). Importantly, pericytes suppress the expression of leukocyte adhesion molecules (LAMs) in BECs to reduce the invasion of immune cells into the CNS, therefore regulating CNS immune surveillance, a critical feature of the mature BBB (6, 7). Thus, as a dynamic interface with a range of interrelated functions, the BBB results from extremely effective TJs, pericyte recruitment, and regulation of leukocyte extravasation, there...

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“…40) The beneficial effects of anti-VEGF neutralizing antibody on t-PA-induced BBB disruption and hemorrhage were also reported. 41) As summarized by Lange et al, 42) VEGF was reported to be a therapeutic target for BBB disruption and a therapeutic target for several other neurological disorders.…”

Section: )mentioning

confidence: 99%

Protection of the Blood–Brain Barrier as a Therapeutic Strategy for Brain Damage

Michinaga

Kōyama

2017

Biological & Pharmaceutical Bulletin

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Severe brain damage by trauma, ischemia, and hemorrhage lead to fatal conditions including sudden death, subsequent complications of the extremities and cognitive dysfunctions. Despite the urgent need for treatments for these complications, currently available therapeutic drugs are limited. Blood-brain barrier (BBB) disruption is a common pathogenic feature in many types of brain damage. The characteristic pathophysiological conditions caused by BBB disruption are brain edema resulting from an excessive increase of brain water content, inflammatory damage caused by infiltrating immune cells, and hemorrhage caused by the breakdown of microvessel structures. Because these pathogenic features induced by BBB disruption cause fatal conditions, their improvement is a desirable strategy. Many studies using experimental animal models have focused on molecules involved in BBB disruption, including vascular endothelial growth factors (VEGFs), matrix metalloproteinases (MMPs) and endothelins (ETs). The inhibition of these factors in several experimental animals was protective against BBB disruption caused by several types of brain damage, and ameliorated brain edema, inflammatory damage, and hemorrhagic transformation. In patients with brain damage, the up-regulation of these factors was observed and was related to brain damage severity. Thus, BBB protection by targeting VEGFs, MMPs, and ETs might be a novel strategy for the treatment of brain damage.

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Vascular endothelial growth factor: a neurovascular target in neurological diseases

Cited by 265 publications

References 199 publications

VEGFR1 and VEGFR2 in Alzheimer’s Disease

VEGFR1 and VEGFR2 in Alzheimer’s Disease

CD146 coordinates brain endothelial cell–pericyte communication for blood–brain barrier development

Protection of the Blood–Brain Barrier as a Therapeutic Strategy for Brain Damage

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