TY - JOUR
T1 - Time Dependent Changes in the Ovine Neurovascular Unit; A Potential Neuroprotective Role of Annexin A1 in Neonatal Hypoxic-Ischemic Encephalopathy
AU - Park, H.Y.
AU - van Bruggen, V.L.E.
AU - Peutz-Kootstra, C.J.
AU - Ophelders, D.R.M.G.
AU - Jellema, R.K.
AU - Reutelingsperger, C.P.M.
AU - Rutten, B.P.F.
AU - Wolfs, T.G.A.M.
N1 - Funding Information:
This work was supported by the Kinderonderzoekfonds Limburg (T.G.A.M.W.), Grant number 2023.
Publisher Copyright:
© 2023 by the authors.
PY - 2023/3/1
Y1 - 2023/3/1
N2 - Perinatal brain injury following hypoxia-ischemia (HI) is characterized by high mortality rates and long-term disabilities. Previously, we demonstrated that depletion of Annexin A1, an essential mediator in BBB integrity, was associated with a temporal loss of blood-brain barrier (BBB) integrity after HI. Since the molecular and cellular mechanisms mediating the impact of HI are not fully scrutinized, we aimed to gain mechanistic insight into the dynamics of essential BBB structures following global HI in relation to ANXA1 expression. Global HI was induced in instrumented preterm ovine fetuses by transient umbilical cord occlusion (UCO) or sham occlusion (control). BBB structures were assessed at 1, 3, or 7 days post-UCO by immunohistochemical analyses of ANXA1, laminin, collagen type IV, and PDGFR beta for pericytes. Our study revealed that within 24 h after HI, cerebrovascular ANXA1 was depleted, which was followed by depletion of laminin and collagen type IV 3 days after HI. Seven days post-HI, increased pericyte coverage, laminin and collagen type IV expression were detected, indicating vascular remodeling. Our data demonstrate novel mechanistic insights into the loss of BBB integrity after HI, and effective strategies to restore BBB integrity should potentially be applied within 48 h after HI. ANXA1 has great therapeutic potential to target HI-driven brain injury.
AB - Perinatal brain injury following hypoxia-ischemia (HI) is characterized by high mortality rates and long-term disabilities. Previously, we demonstrated that depletion of Annexin A1, an essential mediator in BBB integrity, was associated with a temporal loss of blood-brain barrier (BBB) integrity after HI. Since the molecular and cellular mechanisms mediating the impact of HI are not fully scrutinized, we aimed to gain mechanistic insight into the dynamics of essential BBB structures following global HI in relation to ANXA1 expression. Global HI was induced in instrumented preterm ovine fetuses by transient umbilical cord occlusion (UCO) or sham occlusion (control). BBB structures were assessed at 1, 3, or 7 days post-UCO by immunohistochemical analyses of ANXA1, laminin, collagen type IV, and PDGFR beta for pericytes. Our study revealed that within 24 h after HI, cerebrovascular ANXA1 was depleted, which was followed by depletion of laminin and collagen type IV 3 days after HI. Seven days post-HI, increased pericyte coverage, laminin and collagen type IV expression were detected, indicating vascular remodeling. Our data demonstrate novel mechanistic insights into the loss of BBB integrity after HI, and effective strategies to restore BBB integrity should potentially be applied within 48 h after HI. ANXA1 has great therapeutic potential to target HI-driven brain injury.
KW - hypoxic-ischemic encephalopathy
KW - blood-brain barrier (BBB) integrity
KW - neurovascular unit (NVU)
KW - Annexin A1
KW - therapeutic window
KW - CEREBRAL-BLOOD-FLOW
KW - BASEMENT-MEMBRANE
KW - CROSS-LINKING
KW - BRAIN
KW - PERICYTES
KW - HEALTH
KW - IV
KW - PATHOPHYSIOLOGY
KW - GLUCOCORTICOIDS
KW - INFLAMMATION
U2 - 10.3390/ijms24065929
DO - 10.3390/ijms24065929
M3 - Article
C2 - 36983004
SN - 1661-6596
VL - 24
JO - International Journal of Molecular Sciences
JF - International Journal of Molecular Sciences
IS - 6
M1 - 5929
ER -