Table 1 Studies investigating the effects of FGR on the NVU.
Authors | Experimental model | Outcome measured | Key findings |
|---|---|---|---|
Castillo-Melendez et al. (2015)47 | Lambs delivered naturally at term (~145 days) and euthanised 24 h later FGR induced via SUAL at ~105 days gestation | White matter blood vessel density and number EC proliferation Pericyte and astrocyte attachment (coverage of vessels) BBB permeability Microbleeds | Reduced vessel density and number Reduced EC proliferation Reduced pericyte coverage, astrocytic end-feet loss of contact Increased BBB permeability—albumin extravasation and microhaemorrhages |
Castillo-Melendez et al. (2017)44 | Lambs delivered naturally at term (~145 days) and euthanised 24 h later FGR induced via SUAL at ~105 days gestation | Vessel density, proliferation (VEGF) EC proliferation Glut1 Pericyte and astrocyte coverage BBB permeability Microhaemorrhages | Reduced vessel density, proliferation (reduced VEGF expression) Reduced EC proliferation (reduced Glut1 expression) Reduced pericyte and astrocyte end-feet coverage Increased BBB permeability—albumin extravasation and microhaemorrhages |
Chand et al. (2021)49 | Term FGR piglets (<10th percentile birth weight) and NG piglets (10–90th) percentile Euthanasia on postnatal day 4 | Vessel density, vessel length BBB integrity Microglial morphology Pro-inflammatory cytokines Neuronal apoptosis | Reduced vessel density and vascularisation and decrease in vessel branch points FGR showed pro-inflammatory environment with enlarged microglial cell bodies and thickened retracted processes FGR showed significant reductions in neural cells and increased apoptosis |
Chand et al. (2022)48 | Term FGR piglets (<10th percentile birth weight) and NG piglets (10–90th percentile) Euthanasia on postnatal day 4 | Vascular integrity, density Juxtavascular Glial and astrocyte morphology BBB integrity Pro-inflammatory cytokines Apoptosis markers Tight-junction protein ZO-1 | Reduced EC proliferation (reduced endothelial progenitor cells) Altered vascular integrity due to perturbed NVU composition Increased juxtavascular glial activation, increased Iba-1 positive microglia, altered astrocyte end-feet contact Increased frequency of hypertrophic astrocytic end-feet corresponding to decreased astrocytic end-feet coverage of blood vessels Altered BBB permeability and integrity—albumin and IgG extravasation associated with loss of astrocyte end-feet contact with NVU Increased juxtavascular and parenchymal cleaved-caspase 3 labelling, indicated increased apoptosis of astrocytes in NVU BBB disruption—decreased ZO-1 vessel coverage [diffuse and disjointed pattern in FGR vs continuous in NG] |
Giambrone et al. (2019)53 | Sprague-Dawley rats with sham surgery (abdominal incision only) vs induced placental ischaemia (surgical RUPP) on gestational day 14 Fetal brains collected on E19 | Microbleeds—marker of vascular function Neuroinflammation Microglial density and morphology BBB permeability—brain water content | Increased vascular permeability—increased microhaemorrhages in parenchyma Neuroinflammatory state—increased pro-inflammatory cytokines Decreased microglial density in SVZ BBB permeability—surprising no difference in brain water content + contrary negative association between microbleeds and water content |
Malhotra et al. (2018)55 | Lambs delivered at 125 days gestation FGR induced via SUAL at 88 days gestation (term, 150 days) | BBB integrity—RBC, inflammatory cell infiltrate Neuroinflammation—astrogliosis (GFAP-positive staining) BBB integrity—astrocyte barrier disruption, albumin extravasation | Mild RBC infiltration accompanied by perivascular infiltrates of inflammatory cells within white matter consistent with microbleeds; Axonal injury within white matter Similar astrocyte cell counts between FGR and AGA Reactive morphology of astrocytes in FGR compared to AGA Disrupted interaction of astrocyte end-feet with cerebral blood vessels in FGR Albumin extravasation in FGR |
Malhotra et al. (2020)45 | Twin lambs delivered (127 days), intubated and ventilated then euthanised 24 h later FGR induced at 88 days gestation via SUAL in one twin | Neuroinflammation—microglial cell activation EC distribution and numbers through quantifying Glut1 Pericyte coverage BBB function—albumin extravasation | Increased number of activated microglial cells Increased EC coverage Decreased co-localisation with pericyte coverage BBB dysfunction—increased albumin extravasation |
Yawno et al. (2019)54 | Lambs studied at 115d GA, 124d GA, and 1 day postnatal (term is ~147d GA); FGR induced via SUAL at 105d GA | BBB function—microbleeds and albumin extravasation Astrocyte end-feet attachment, astrocyte density Neuroinflammatory response—microglial cell number | BBB dysfunction—blue staining and microbleeds present BBB dysfunction—albumin extravasation observed in all regions of cerebellum, especially adjacent to blood vessels Decreased end-feet of astrocytes associated with blood vessels, decreased astrocyte density in 124d GA Pro-inflammatory state—increase in microglial cell numbers at 124d GA |
