Abstract
Background: Vascular endothelial growth factor (VEGF) stimulates vascular genesis and angiogenesis. Cerebral Hypoxia-Ischemia (HI) leads to the reduction of vasculature in the cerebral cortex of newborn piglets. Objective: The present study tests the hypothesis that post-hypoxia intranasal administration of recombinant human VEGF165 (rh-VEGF165) for 3 days increases the vascular density in the cerebral cortex of newborn piglets without promoting neovascularization. Design/Methods: Ventilated newborn piglets were divided into three groups (n = 5/group): normoxic (Nx), hypoxic-ischemic (HI), and HI treated with intranasal rh-VEGF165rh-VEGF165 (HI-VEGF). HI piglets were exposed to HI (0.05 FiO2) for 30 min. Recombinant h-VEGF165 (100 ng/kg) was administered 15 min after HI and then once daily for 3 days. The animals were perfused transcardially and coronal brains sections were processed for Isolectin, Hoechst, and ki-67 cell proliferation marker staining. To assess the vascular density, 30–35 fields per animal section were manually counted using image J software. Results: The vascular density (vessels/mm2) was 42.0 ± 8.0 in the Nx group, 26.4 ± 4.8 (p < 0.05 vs. Nx) in the HI group, and 46.0 ± 11.9 (p < 0.05 vs. HI) in the HI-VEGF group. When stained for newly formed vessels, via Ki-67 staining, the vascular density was 5.4 ± 3.6 in the Nx group (p < 0.05 vs. HI), 10.2 ± 2.1 in the HI group, and 10.9 ± 2.9 in the HI-VEGF group (p = 0.72 vs. HI). HI resulted in a decrease in vascular density. Intranasal rh-VEGF165rh-VEGF165 resulted in the attenuation of the HI-induced decrease in vascular density. However, rh-VEGF165 did not result in the formation of new vascularity, as evident by ki-67 staining. Conclusions: Intranasal rh-VEGF165 may prevent the HI-induced decrease in the vascular density of the brain and could serve as a promising adjuvant therapy for hypoxic-ischemic encephalopathy (HIE).
Highlights
Hypoxic–ischemic (HI) injury to the prenatal and perinatal brain is a major contributor to global child mortality and morbidity [1,2,3,4]
In an attempt to minimize the possible systemic toxicity of the rh-VEGF165 and achieve rapid administration at the time of birth, the current study aims to investigate the effect of intranasally
Our laboratory [26] and other investigators [25,27,28,29,30,31,32,33,34,35,36,37] have used the newborn piglet model as it provides the advantage of real-time measurements of physiologic parameters such as arterial blood gases and continuous blood pressure monitoring, which allows titration of FiO2 to achieve a precise and reproducible degree of hypoxia-ischemia [25,27,32,38]
Summary
Hypoxic–ischemic (HI) injury to the prenatal and perinatal brain is a major contributor to global child mortality and morbidity [1,2,3,4]. Perinatal hypoxic–ischemic injury affects between 1 and 8 per 1000 full-term infants and nearly 60% of low birth-weight premature infants [2]. Objective: The present study tests the hypothesis that post-hypoxia intranasal administration of recombinant human VEGF165 (rh-VEGF165) for 3 days increases the vascular density in the cerebral cortex of newborn piglets without promoting neovascularization. Results: The vascular density (vessels/mm2) was 42.0 ± 8.0 in the Nx group, 26.4 ± 4.8 (p < 0.05 vs Nx) in the HI group, and 46.0 ± 11.9 (p < 0.05 vs HI) in the HI-VEGF group. HI resulted in a decrease in vascular density. Intranasal rh-VEGF165rh-VEGF165 resulted in the attenuation of the HI-induced decrease in vascular density. Conclusions: Intranasal rh-VEGF165 may prevent the HI-induced decrease in the vascular density of the brain and could serve as a promising adjuvant therapy for hypoxic-ischemic encephalopathy (HIE)
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