Mechanisms of intermittent hypoxia induced hypertension

Abstract

Exposing rodents to brief episodes of hypoxia mimics the hypoxemia and the cardiovascular and metabolic effects observed in patients with obstructive sleep apnoea (OSA), a condition that affects between 5% and 20% of the population. Apart from daytime sleepiness, OSA is associated with a high incidence of systemic and pulmonary hypertension, peripheral vascular disease, stroke and sudden cardiac death. The development of animal models to study sleep apnoea has provided convincing evidence that recurrent exposure to intermittent hypoxia (IH) has significant vascular and haemodynamic impact that explain much of the cardiovascular morbidity and mortality observed in patients with sleep apnoea. However, the molecular and cellular mechanisms of how IH causes these changes is unclear and under investigation. This review focuses on the most recent findings addressing these mechanisms. It includes a discussion of the contribution of the nervous system, circulating and vascular factors, inflammatory mediators and transcription factors to IH-induced cardiovascular disease. It also highlights the importance of reactive oxygen species as a primary mediator of the systemic and pulmonary hypertension that develops in response to exposure to IH.

Fig 1

MAP was recorded daily for 3 baseline days and 14 treatment days in eucapnic intermittent hypoxia (IH-C) ± Tempol and Sham ± Tempol (T). MAP increased in IH-C-vehicle rats over the 14 days of treatment. MAP did not increase in IH-C rats treated with Tempol (1 mM). Tempol did not affect MAP in sham-operated rats. *P < 0.05, significant difference from Sham/vehicle. Reprinted with permission from Carmen M. Troncoso Brindeiro et al. [63].

Fig 2

MAP values, including those for the day before IH exposure (day 0 = air exposure), for NFATc3 wild-type and knockout mice. *P < 0.05 versus knockout; #P < 0.05 versus day 0 (two-way repeated-measures anova and Holm–Sidak test). Reprinted with permission from Sergio de Frutos et al. [29].

Fig 3

Proposed mechanisms of IH-induced pulmonary hypertension. ET-1, ROS and HIF-1 may play important roles in the vasoconstrictor, remodelling and polycythemic components of pulmonary hypertension. Supplemental CO₂ blunts IH-induced right ventricular hypertrophy, arterial remodelling and polycythemia.

Fig 4

Working model of the mechanisms of IH-induced hypertension. ROS = reactive oxygen species; ET-1 = endothelin-1; ANG II = angiotensin II; HIF-1 = hypoxia inducible factor-1; NF-κB = nuclear factor-κ-light chain enhancer of activated B cells; NFAT = nuclear factor of activated T cells.