VEGF expression and microvascular responses to severe transient hypoxia in the fetal sheep brain

Baburamani, Ana A.; Castillo‐Melendez, Margie; Walker, David

doi:10.1038/pr.2012.191

Cited by 31 publications

(42 citation statements)

References 38 publications

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“…Increased density of proliferating brain capillaries was observed as early as day 3 up to 2 weeks after hypoxia and ischemia (15, 16). Vascular endothelial growth factor (VEGF) is an important mediator of capillary proliferation; it is upregulated after hypoxic-ischemic insults and it is involved in angiogenesis, neurogenesis, and neuronal survival during the recovery process (17, 18). Disruption of the VEGF signaling pathway alters angiogenesis after recovery from hypoxic-ischemic brain injury in rodents (17, 19).…”

Section: Introductionmentioning

confidence: 99%

“…In the adult brain, basic fibroblast growth factor (FGF-2, bFGF) is another growth factor that has been shown to augment angiogenesis after ischemia (20, 21). Although numerous studies have characterized the neuronal response to a variety of ischemic insults in the fetal brain (22), there is very little information on the effects of ischemia-reperfusion related injury on neovascularization in the cerebral cortex in the fetal brain (18, 23). …”

Section: Introductionmentioning

confidence: 99%

“…We have previously shown that brain ischemia in the ovine fetus results in reproducible cerebral cortical and white matter lesions, increases in cerebral cortical FGF-2 levels, and increases in blood-brain barrier permeability along with concomitant alterations in the molecular composition of endothelial cell tight junctions (4, 29). In addition, a recent study has shown that by 48 hours after umbilical cord occlusion, the percentage of blood vessels expressing VEGF increased in several brain regions (18). The rationale for the current study is that, although angiogenesis is an important component in fetal brain development (11, 30) and increases have been documented after ischemia and stroke in the adult brain (31), the effects of ischemia-reperfusion-related brain injury on the potential for neovascularization are less well understood in the fetal brain.…”

Section: Introductionmentioning

confidence: 99%

“…In addition, the timing of the onset of neovascularization after injury has not been well established in the fetal brain. Knowledge regarding the responses of the immature vasculature to injury could be important to the development of therapies for hypoxic-ischemic injury in the immature brain (18, 23). Therefore, the objective of the current study was to test the hypothesis that ischemia-reperfusion induces neovascularization in the cerebral cortex of the ovine fetus.…”

Section: Introductionmentioning

confidence: 99%

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Ischemia/Reperfusion-Induced Neovascularization in the Cerebral Cortex of the Ovine Fetus

Virgintino

Girolamo

Rizzi

et al. 2014

J Neuropathol Exp Neurol

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Information is limited regarding the effects of injury on neovascularization in the immature brain. We investigated effects of ischemia on cerebral cortical neovascularization after exposure of fetuses to 30 minutes of cerebral ischemia and 48- (I/R-48) or 72- (I/R-72) hours of reperfusion or sham-control treatment (Non-I/R). Immunohistochemical and morphometric analyses of cerebral cortical sections included immunostaining for glial fibrillary acidic protein and collagen type IV (Coll IV), a molecular component of the vascular basal lamina, to determine the glial-vascular network in fetal brains, and Ki67 as a proliferation marker. Cerebral cortices from I/R-48 and I/R-72 fetuses exhibited general responses to ischemia, including reactive astrocyte morphology, which was not observed in Non-I/R fetuses. Cell bodies of reactive, proliferating astrocytes along with large end-feet surrounded walls of cerebral cortical microvessels in addition to the thick Coll IV-enriched basal lamina. Morphometric analysis of Non-I/R with I/R-48 and I/R-72 groups revealed increased Coll IV density in I/R-72 cerebral cortical microvessels (p < 0.01), which also frequently displayed a sprouting appearance, characterized by growing tip cells and activated pericytes. Increases in cerebral cortical basic fibroblast growth factor were associated with neovascularization. We conclude that increased neovascularization occurs within 72 hours after ischemia in fetal cerebral cortices.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Ischemia/Reperfusion-Induced Neovascularization in the Cerebral Cortex of the Ovine Fetus

Virgintino

Girolamo

Rizzi

et al. 2014

J Neuropathol Exp Neurol

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“…Ltd., Australia) in oxygen and nitrous oxide (70: 30). Under aseptic conditions, the uterus was exposed, and a catheter (inner diameter 0.8 mm, outer diameter 1.5 mm, Dural Plastics, Australia) containing 0.9% saline and heparin (25 325 Australia, West Ryde, NSW, Australia) was inserted into the fetal femoral artery. We induced placental insufficiency and subsequent FGR in a cohort of animals via single umbilical-artery ligation (SUAL), which involves placing 2 silk ligatures tightly around 1 of the umbilical arteries.…”

Section: Animal Surgery and Maintenancementioning

confidence: 99%

Effects of Antenatal Melatonin Treatment on the Cerebral Vasculature in an Ovine Model of Fetal Growth Restriction

et al. 2017

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Chronic moderate hypoxia, such as occurs in fetal growth restriction (FGR) during gestation, compromises the blood-brain barrier (BBB) and results in structural abnormalities of the cerebral vasculature. We have previously determined the neuroprotective and antioxidant effects of maternal administration of melatonin (MLT) on growth-restricted newborn lambs. The potential of maternal MLT therapy for the treatment of cerebrovascular dysfunction-associated developmental hypoxia has also been demonstrated in newborn lambs. We assessed whether MLT had an effect on the previously reported structural and cerebral vascular abnormalities in chronically hypoxic FGR lambs. Single umbilical-artery ligation surgery was performed in fetuses at approximately 105 days of gestation (term: 147 days) to induce placental insufficiency and FGR, and treatment with either saline or an MLT infusion (0.1 mg/kg) was started 4 h after surgery. Ewes delivered naturally at term and lambs were euthanased 24 h later. We found a significant reduction in the number of laminin-positive blood vessels within the subcortical and periventricular white matter (SCWM and PVWM) and the subventricular zone (SVZ) in FGR (p < 0.0005) and FGR + MLT brains (p < 0.0005 vs. controls), with no difference found between FGR and FGR + MLT animals. This was associated with a significant decrease in VEGF immunoreactivity in FGR and FGR + MLT brains versus controls (p < 0.0005; SCWM and PVWM) and in the SVZ in FGR brains versus controls (p < 0.005) and also with significantly lower levels of proliferating blood vessels versus controls (p < 0.0005). Glucose transporter-1 immunoreactivity (vascular endothelium) was decreased in FGR versus control lambs (p < 0.0005) in SCWM, PVWM, and the SVZ; it was significantly increased in FGR + MLT lambs compared with FGR lambs in SCWM and PVWM (p < 0.005) and even more markedly in the SVZ (p < 0.0005). FGR brains showed a 72% reduction in pericyte coverage versus control lambs and 68% versus FGR + MLT in PVWM. In SCWM, we found a 77 and 73% reduction compared with control and FGR + MLT lambs, respectively, while in the SVZ, we observed a 68% reduction versus controls and a 70% reduction in FGR versus FGR + MLT lambs. Astrocyte end-feet coverage in the SCWM showed a significant 24% reduction in FGR versus control levels, a 42% decrease within the PVWM, and a 35% decrease within the SVZ versus controls. MLT normalized astrocyte attachment to blood vessels, with no difference seen between controls and FGR + MLT animals in any of the brain regions examined. We also observed a decrease in albumin extravasation and microhemorrhage in controls and FGR + MLT brains versus FGR lambs. Our results demonstrate that umbilicoplacental insufficiency is associated with FGR-produced vascular changes in the white matter and SVZ of FGR newborn brains and that maternal MLT prevented disruption of the BBB by protecting perivascular cells essential for the maintenance of vascular homeostasis and stability.

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Self‐Oxygenation of Tissues Orchestrates Full‐Thickness Vascularization of Living Implants

Farzin

Hassan

Teixeira

et al. 2021

Adv Funct Materials

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Bioengineering of tissues and organs has the potential to generate functional replacement organs. However, achieving the full-thickness vascularization that is required for long-term survival of living implants has remained a grand challenge, especially for clinically sized implants. During the pre-vascular phase, implanted engineered tissues are forced to metabolically rely on the diffusion of nutrients from adjacent host-tissue, which for larger living implants results in anoxia, cell death, and ultimately implant failure. Here it is reported that this challenge can be addressed by engineering self-oxygenating tissues, which is achieved via the incorporation of hydrophobic oxygen-generating micromaterials into engineered tissues. Self-oxygenation of tissues transforms anoxic stresses into hypoxic stimulation in a homogenous and tissue sizeindependent manner. The in situ elevation of oxygen tension enables the sustained production of high quantities of angiogenic factors by implanted cells, which are offered a metabolically protected pro-angiogenic microenvironment. Numerical simulations predict that self-oxygenation of living tissues will effectively orchestrate rapid full-thickness vascularization of implanted tissues, which is empirically confirmed via in vivo experimentation. Self-oxygenation of tissues thus represents a novel, effective, and widely applicable strategy to enable the vascularization living implants, which is expected to advance organ transplantation and regenerative medicine applications.

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VEGF expression and microvascular responses to severe transient hypoxia in the fetal sheep brain

Cited by 31 publications

References 38 publications

Ischemia/Reperfusion-Induced Neovascularization in the Cerebral Cortex of the Ovine Fetus

Ischemia/Reperfusion-Induced Neovascularization in the Cerebral Cortex of the Ovine Fetus

Effects of Antenatal Melatonin Treatment on the Cerebral Vasculature in an Ovine Model of Fetal Growth Restriction

Self‐Oxygenation of Tissues Orchestrates Full‐Thickness Vascularization of Living Implants

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