Review: The blood-brain barrier; protecting the developing fetal brain

Abstract

While placental function is fundamental to normal fetal development, the blood-brain barrier provides a second checkpoint critical to protecting the fetal brain and ensuring healthy brain development. The placenta is considered the key barrier between the mother and fetus, regulating delivery of essential nutrients, removing waste as well as protecting the fetus from potentially noxious substances. However, disturbances to the maternal environment and subsequent adaptations to placental function may render the placenta ineffective for providing a suitable environment for the developing fetus and to providing sufficient protection from harmful substances. The developing brain is particularly vulnerable to changes in the maternal/fetal environment. Development of the blood-brain barrier and maturation of barrier transporter systems work to protect the fetal brain from exposure to drugs, excluding them from the fetal CNS. This review will focus on the role of the 'other' key barrier during gestation - the blood-brain barrier - which has been shown to be functional as early as 8 weeks' gestation.

Zika Virus Persistently Infects and Is Basolaterally Released from Primary Human Brain Microvascular Endothelial Cells

“…hBMECs form a protective blood-brain barrier that restricts viral access to neuronal compartments (18), and mechanisms by which ZIKV bypasses the BBB remain to be defined. We initially assessed the ability of early-passage ZIKV (PRVABC59) to infect primary hBMECs (passages 3 to 10) by immunoperoxidase staining ZIKV-infected cells.…”

“…hBMECs form a BBB that prevents paracellular permeability and that in vivo restricts access of blood constituents to neuronal compartments (17, 18). We evaluated changes in the barrier function of hBMECs following ZIKV infection by assessing the transendothelial electrical resistance (TEER) (58) and fluorescein isothiocyanate (FITC)-dextran permeability (59) of hBMEC monolayers grown on Transwell inserts.…”

“…ECs control immune cell recruitment, targeting, and transcytosis into tissues and perform primary fluid barrier functions that prevent capillary leakage. ECs innervate and protect immune-restricted compartments from viral spread (17), and emigration across ECs is required for ZIKV to bypass blood-retina barriers and blood-testicle barriers to infect retinal ganglion cells, aqueous humor, the cornea, Sertoli cells, seminiferous tubules, and spermatagonia (18, 43, 44). ECs express tolerizing PD-L1 receptors that prevent immune targeting of the endothelium and which may foster viral immune evasion and persistence (85).…”

“…ZIKV infects fetal and maternal cells, including neural stem cells, astrocytes, neuronal progenitor cells, microglia, Hofbauer cells, and endothelial cells (ECs) (6, 11–16). ZIKV crosses placental and blood-brain barrier (BBB) ECs, cells which normally prevent mixing of maternal and fetal blood and restrict access to adult and fetal neuronal compartments (17, 18). …”

“…ECs serve a primary barrier function that normally limits the access of blood constituents to the privileged neuronal, retinal, testicular, and placental compartments (18, 43–45). Brain capillaries form a BBB composed of unique brain microvascular ECs (BMECs), which restrict the emigration of immune cells and viruses to neuronal compartments (17, 46).…”