HIF-1 at the Blood-Brain Barrier: A Mediator of Permeability?

Abstract

The importance of the blood-brain barrier (BBB) in maintaining brain homeostasis cannot be better appreciated than during disease states, where disruption of its function is associated with dramatic detrimental clinical outcome. For decades, neuroscientists and neurobiologists investigated most neurological diseases under the prism of a neuro-centric view, considering the contribution of nonneural components of the CNS (BBB, choroid plexus) negligible or even irrelevant. However, recent reviews have highlighted the importance of BBB breakdown in major neurological diseases. Hypoxia, as well as hypoxia/reoxygenation, are key components of many neurological diseases and have been shown to contribute to barrier disturbance and dysfunction significantly. Since the master regulator of the hypoxic response, hypoxia inducible factor 1 (HIF-1), is a key determinant for adaptation of cells and tissues to oxygen deprivation, it is likely that this transcription factor also plays a key role in barrier permeability. The possible future use of HIF-1 stabilizers for treatment of diseases characterized by oxygen deprivation to increase neuronal/cell survival means this question is now very pertinent. This review will focus its attention on the role of HIF-1 in BBB breakdown following hypoxic/ischemic injury and the implications for such therapies in a clinical setting. AbstractThe importance of the blood-brain barrier (BBB) in maintaining brain homeostasis

Heart failure and cognitive dysfunction

“…The development and maintenance of these junctional proteins is dependent on a variety of proteins produced by astrocytes and pericytes. Hypoxia results in the release of hypoxia inducible factor-1 (HIF-1) [81,82]. In the presence of hypoxia, HIF-1 translocates from the cytoplasm to the nucleus where it binds to hypoxia-responsive elements resulting in the expression of a variety of genes involved in the adaptation to hypoxia.…”

Cerebral Vascular Control and Metabolism in Heat Stress

“…These larger agents must, therefore, be regulated by transport proteins (e.g., GLUT1 for the passage of glucose) and by receptor-and adsorptive-mediated transcytosis (e.g., for insulin) (3)(4)(5). A range of physiological and pathological conditions readily alter transport across the BBB, including starvation (46), hypoxia (339) and heat stress (408). Indeed, BBB transport is far from static (207), while obvious consequences, including vasogenic edema, result from uncontrolled BBB opening.…”

The influence of a mild thermal challenge and severe hypoxia on exercise performance and serum BDNF

“…Two studies looked at the effects of chronic altitude exposure for at least 72 h (Li et al 2012;Helan et al 2014). Their outcomes are contradictory, Li et al (2012) showed a decrease in BDNF concentration after a 5-day acclimatization period at 3900 m, while Helan et al (2014) observed increased BDNF levels after 72 h at 3350 m. Both hypoxia and BDNF increased hypoxia-inducible factor 1 (Helan et al 2014), a factor that is considered as an important regulator in the hypoxic response of the BBB (Ogunshola and Al-Ahmad 2012). The discrepancy in these findings and the lack of effect on an acute exposure, as observed in the present study, elucidate the necessity for further research on the effects of altitude on BDNF, and the potential mechanisms involved.…”