Effects of Hypoxia on Cerebral Microvascular Angiogenesis: Benefits or Damages?

Abstract

Cerebrovascular microcirculation is essential for maintaining the physiological functions of the brain. The brain can be protected from stress injury by remodeling the microcirculation network. Angiogenesis is a type of cerebral vascular remodeling. It is an effective approach to improve the blood flow of the cerebral microcirculation, which is necessary for preventing and treating various neurological disorders. Hypoxia is one of the most important regulators of angiogenesis, affecting the sprouting, proliferation, and maturation stages of angiogenesis. Moreover, hypoxia negatively affects cerebral vascular tissue by impairing the structural and functional integrity of the blood-brain barrier and vascular-nerve decoupling. Therefore, hypoxia has a dual effect on blood vessels and is affected by confounding factors including oxygen concentration, hypoxia duration, and hypoxia frequency and extent. Establishing an optimal model that promotes cerebral microvasculogenesis without causing vascular injury is essential. In this review, we first elaborate on the effects of hypoxia on blood vessels from two different perspectives: (1) the promotion of angiogenesis and (2) cerebral microcirculation damage. We further discuss the factors influencing the dual role of hypoxia and emphasize the benefits of moderate hypoxic irritation and its potential application as an easy, safe, and effective treatment for multiple nervous system disorders.

Keywords: angiogenesis; cerebrovascular microcirculation; endothelial cells; hypoxia; intermittent hypoxia.

Figure 1.

Stages of angiogenesis. (A) Quiescent endothelial cells (ECs): mature capillaries consist of quiescent ECs surrounded by mural cells and basement membranes. (B) Endothelial activation: in response to hypoxia stimulation, vascular endothelial growth factor-A (VEGF-A) activates matrix metalloproteinases (MMPs), and other factors are increased and bind to corresponding receptors, resulting in the degradation of the basement membrane and detachment of pericytes and polarization of ECs. (C) Sprouting: tip cells and stalk cells are selectively differentiated under the stimulation of different angiogenic factors. (D) Guidance and lumen formation: (1) tip cells navigate following the VEGF-A concentration gradient while stalk cells elongate and proliferate; (2) vascular endothelial cadherin facilitates tip cell anastomosis between branches; and (3) lumen formation is due to intercellular polarity rejection. (E) Vessel maturation and perfusion: (1) mural cells in the vessels are recruited and the basement membrane reforms. (2) Upon perfusion, active stalk cells dynamically change shape and oxygen reduces VEGF-A expression shifting endothelial behavior toward a quiescent phenotype.

Figure 2.

Schematic of the role of hypoxia. The balance of critical factors determines beneficial vs. pathogenic roles of hypoxia on the cerebral microvasculature. The hypoxic intervention (5-8% O₂, more than 50 cycles/day or more than 8 h/day) is prone to neurological damage. Quite mild hypoxia (15-21% O₂; less than 2 h/day) does not stimulate angiogenesis. In contrast, moderate hypoxia (10-15% O₂; 2~8 h/day; <15 cycles/day) seems to contribute to beneficial (potentially “therapeutic”) effects with minimal nerve damage (shaded in blue).