Angiogenic inhibition reduces germinal matrix hemorrhage

Ballabh, Praveen; Xu, Hongmin; Hu, Furong; Braun, Alex; Smith, Kira; Rivera, Aracelie; Lou, Nanhong; Ungvári, Zoltán; Goldman, Steven A.; Csiszár, Anna; Nedergaard, Maiken

doi:10.1038/nm1558

Cited by 140 publications

(176 citation statements)

References 41 publications

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“…Therefore, to further elucidate the mechanism underlying lesser pericyte recruitment in the GM vasculature, we compared the levels of these growth factors and their receptors among the GM, cortex, and white matter. We described previously that Ang-1 and Tie-2 levels are comparable among these three brain regions (Ballabh et al, 2007).…”

Section: Growth Factors Recruiting Pericytes In Human Fetuses and Prementioning

confidence: 72%

“…In the present study, for the sake of uniformity and consistency of presentation, white matter refers to intermediate zone embryonic white matter, and cortex refers to neocortical mantle. Brain samples were processed as described previously (Ballabh et al, 2007). Briefly, we obtained 3-to 4-mm-thick coronal blocks by sectioning through frontal cortex, frontal white matter, and GM in the region of thalamostriate groove and at the level of foramen of Monro.…”

Section: Methodsmentioning

confidence: 99%

“…We could not obtain satisfactory immunostaining with the commercially available PDGFR-␤ antibody in rabbit brain samples, and thus immunohistochemistry for PDGFR-␤ in rabbit tissues was precluded from the study. Immunolabeling with primary antibodies was done sequentially for double and triple labeling, as described previously (Ballabh et al, 2007).…”

Section: Methodsmentioning

confidence: 99%

“…Total RNA was reverse transcripted to cDNAs by using SuperScript First-Strand Synthesis System for RT-PCR kit (catalog #11904-018; Invitrogen) following the manufacturer's protocol. Real-time PCR was used to quantify mRNA expression using the Stratagene (Bernried, Germany) MX3000 on the cDNA as described (Ballabh et al, 2007). Samples were run in triplicate.…”

Section: Methodsmentioning

confidence: 99%

“…More importantly, we reported that a rapid angiogenesis in the GM, induced by high vascular endothelial growth factor (VEGF) and angiopoietin (ANGPT)-2 levels, is associated with greater vascular fragility and propensity to hemorrhage, and that angiogenic inhibition reduces both the incidence and the severity of GMH in rabbit pup model (Ballabh et al, 2007). Angiogenesis involves formation of nascent blood vessels, which are subsequently stabilized by pericytes.…”

Section: Introductionmentioning

confidence: 99%

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Paucity of Pericytes in Germinal Matrix Vasculature of Premature Infants

et al. 2007

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Germinal matrix (GM) is a richly vascularized collection of neuronal-glial precursor cells in the developing brain, which is selectively vulnerable to hemorrhage in premature infants. It has rapid angiogenesis associated with high levels of vascular endothelial growth factor (VEGF). Because pericytes provide structural stability to blood vessels, we asked whether pericytes were fewer in the GM than in the subjacent white matter and neocortex and, if so, whether angiogenic inhibition could increase the pericyte density in the GM. We found pericyte coverage and density less in the GM vasculature than in the cortex or white matter in human fetuses, premature infants, and premature rabbit pups. Notably, although VEGF suppression significantly enhanced pericyte coverage in the GM, it remained less than in other brain regions. Therefore, to further elucidate the basis of fewer pericytes in the GM vasculature, we examined expression of ligand-receptor systems responsible for pericyte recruitment. Transforming growth factor-␤1 (TGF-␤1) protein expression was lower, whereas sphingosine-1-phosphate1 (S1P1) and N-cadherin levels were higher in the GM than in the cortex or white matter. Low TGF-␤1 may be involved in promoting endothelial proliferation, whereas elevated S1P1 with N-cadherin may assist vascular maturation. Hence, a paucity of pericytes in the GM vasculature may contribute to its propensity to hemorrhage, and a lower expression of TGF-␤1 could be a basis of reduced pericyte density in its vasculature.

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Section: Growth Factors Recruiting Pericytes In Human Fetuses and Prementioning

confidence: 72%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Paucity of Pericytes in Germinal Matrix Vasculature of Premature Infants

et al. 2007

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Subcutaneous reservoir drainage versus ventriculoperitoneal shunt for the treatment of posthemorrhagic hydrocephalus in preterm infants

Zhou

et al. 2009

Cochrane Database of Systematic Reviews

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Opposite effect of inflammation on subventricular zone versus hippocampal precursors in brain injury

Covey

Loporchio

Buono

et al. 2011

Annals of Neurology

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Objective Inflammation promotes epidermal wound healing but is considered detrimental to recovery from CNS injury. Sick infants have increased levels of cytokines in their CSF that correlate with poor neurological outcome. In this study we investigated the role of neuroinflammation and more specifically, IL-6, in the amplification of subventricular zone (SVZ) and subgranular zone (SGZ) neural precursors after neonatal brain injury. Methods Neonatal hypoxia/ischemia (H/I) was induced in P6 rat pups and IL-6 was quantified with or without Indomethacin administration. Neural precursor responses were evaluated by neurosphere assays as well as by stereological analyses. Studies were performed to determine how IL-6 and LIF affect SVZ cell expansion, proliferation and self-renewal. Results Consistent with earlier studies, SVZ cells expanded after H/I. Contrary to our expectations, Indomethacin significantly decreased both the initial reactive increase in these precursors as well as their ability to self-renew. By contrast, Indomethacin increased proliferation in the SGZ and lateral SVZ. Indomethacin diminished the accumulation of microglia/macrophages and IL-6 production after H/I. In vitro IL-6 enhanced neurosphere growth, self-renewal and tripotentiality and was more effective than LIF in promoting self-renewal. Enhanced precursor self-renewal also was obtained using PGE2, which is downstream of cyclooxygenase-2 and a target of Indomethacin. Interpretation These data implicate neuroinflammation and in particular IL-6 as a positive effector of primitive neural precursor expansion after neonatal brain injury. These findings have important clinical implications, as Indomethacin and other anti-inflammatory agents are administered to premature infants for a variety of reasons.

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Angiogenic inhibition reduces germinal matrix hemorrhage

Cited by 140 publications

References 41 publications

Paucity of Pericytes in Germinal Matrix Vasculature of Premature Infants

Paucity of Pericytes in Germinal Matrix Vasculature of Premature Infants

Subcutaneous reservoir drainage versus ventriculoperitoneal shunt for the treatment of posthemorrhagic hydrocephalus in preterm infants

Opposite effect of inflammation on subventricular zone versus hippocampal precursors in brain injury

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