Vulnerability of the developing brain to hypoxic-ischemic damage: contribution of the cerebral vasculature to injury and repair?

Abstract

As clinicians attempt to understand the underlying reasons for the vulnerability of different regions of the developing brain to injury, it is apparent that little is known as to how hypoxia-ischemia may affect the cerebrovasculature in the developing infant. Most of the research investigating the pathogenesis of perinatal brain injury following hypoxia-ischemia has focused on excitotoxicity, oxidative stress and an inflammatory response, with the response of the developing cerebrovasculature receiving less attention. This is surprising as the presentation of devastating and permanent injury such as germinal matrix-intraventricular haemorrhage (GM-IVH) and perinatal stroke are of vascular origin, and the origin of periventricular leukomalacia (PVL) may also arise from poor perfusion of the white matter. This highlights that cerebrovasculature injury following hypoxia could primarily be responsible for the injury seen in the brain of many infants diagnosed with hypoxic-ischemic encephalopathy (HIE). Interestingly the highly dynamic nature of the cerebral blood vessels in the fetus, and the fluctuations of cerebral blood flow and metabolic demand that occur following hypoxia suggest that the response of blood vessels could explain both regional protection and vulnerability in the developing brain. However, research into how blood vessels respond following hypoxia-ischemia have mostly been conducted in adult models of ischemia or stroke, further highlighting the need to investigate how the developing cerebrovasculature responds and the possible contribution to perinatal brain injury following hypoxia. This review discusses the current concepts on the pathogenesis of perinatal brain injury, the development of the fetal cerebrovasculature and the blood brain barrier (BBB), and key mediators involved with the response of cerebral blood vessels to hypoxia.

Keywords: angiogenesis; blood-brain barrier; cerebral blood vessels; hemorrhage; hypoxia.

Figure 1

Diagram summarizing the actions of VEGF. VEGF is involved in numerous important physiological processes. Angiogenesis is the main function of VEGF, however, it also has protective actions (shown in blue) which include neurogenesis and involvement during development, and detrimental actions (shown in red) including being a pro-inflammatory mediator, vascular permeability factor and involved in tumor growth.

Figure 2

Schematic diagram of the effects of VEGF following hypoxia. Following hypoxia, increased VEGF expression stimulated angiogenesis leading to increase vascularization. Increased VEGF expression can have detrimental effects (shown in red) which can lead to edema and haemorrhage formation. Beneficial effects of increased VEGF (shown in blue) help stimulate neurogenesis, decrease apoptosis and are neuroprotective.

Figure 3

Summary of the consequence of hypoxia and/or ischemia on the neurovascular unit. Following hypoxia, endothelial cells express a range of key hypoxic and angiogenic factors, basement membrane degradation occurs, astrocyte end-feet become swollen, modulation of tight junction expression occur and pericytes may migrate away. These responses contribute to angiogenesis, vascular remodeling, edema, and hemorrhage formation, increased vascular permeability, and decreased vascular stability.