Maladaptive Pulmonary Vascular Responses to Chronic Sustained and Chronic Intermittent Hypoxia in Rat

Abstract

Chronic sustained hypoxia (CSH), as found in individuals living at a high altitude or in patients suffering respiratory disorders, initiates physiological adaptations such as carotid body stimulation to maintain oxygen levels, but has deleterious effects such as pulmonary hypertension (PH). Obstructive sleep apnea (OSA), a respiratory disorder of increasing prevalence, is characterized by a situation of chronic intermittent hypoxia (CIH). OSA is associated with the development of systemic hypertension and cardiovascular pathologies, due to carotid body and sympathetic overactivation. There is growing evidence that CIH can also compromise the pulmonary circulation, causing pulmonary hypertension in OSA patients and animal models. The aim of this work was to compare hemodynamics, vascular contractility, and L-arginine-NO metabolism in two models of PH in rats, associated with CSH and CIH exposure. We demonstrate that whereas CSH and CIH cause several common effects such as an increased hematocrit, weight loss, and an increase in pulmonary artery pressure (PAP), compared to CIH, CSH seems to have more of an effect on the pulmonary circulation, whereas the effects of CIH are apparently more targeted on the systemic circulation. The results suggest that the endothelial dysfunction evident in pulmonary arteries with both hypoxia protocols are not due to an increase in methylated arginines in these arteries, although an increase in plasma SDMA could contribute to the apparent loss of basal NO-dependent vasodilation and, therefore, the increase in PAP that results from CIH.

The Cardiovascular and Metabolic Effects of Chronic Hypoxia in Animal Models: A Mini-Review

“…Both CSH and CIH in animal models have been used to simulate various disease states. CSH has been applied to rodents at varying fraction of inspired oxygen (FiO 2 ), generally ranging from 0.10 to 0.15 ( Hislop and Reid, 1976 ; Cowburn et al, 2017 ; Ioja et al, 2018 ; Prieto-Lloret et al, 2021 ), either been normobaric or hypobaric relative to sea level. Though resulting peripheral saturations are not always considered, the severity of CSH is a critical variable: For instance, CSH of FiO 2 0.10 as a model of high altitude exposure might recapitulate the effective oxygen content at an altitude of 5800 m (Mt.…”

Understanding human aging and the fundamental cell signaling link in age-related diseases: the middle-aging hypovascularity hypoxia hypothesis

“…Chronic (continuous, non-interrupted, and sustained) and cyclic (intermittent and transient) hypoxia, which are characterized by fluctuations in oxygen levels ( Bader et al, 2020 ), have been linked to the development of human diseases and cancer ( Saxena and Jolly, 2019 ; Chen et al, 2020 ; Liu et al, 2022 ). Chronic sustained hypoxia (CSH) seems to compromise the pulmonary circulation and carotid body stimulation to maintain oxygen levels, whereas the effects of chronic intermittent hypoxia (CIH) appear to be more targeted on the systemic circulation ( Prieto-Lloret et al, 2021 ).…”

Oxygen Sensing: Physiology and Pathophysiology

“…They demonstrate that, while CSH and CIH cause several common effects, such as increased hematocrit, weight loss, and increased pulmonary arterial pressure (PAP), CSH appears to have a greater effect on the pulmonary circulation, whereas the effects of CIH are apparently more directed to the systemic circulation. Furthermore, their results suggest that the endothelial dysfunction evident in pulmonary arteries with both hypoxia protocols is not due to an increase in methylated arginines in these arteries, although an increase in plasma SDMA could contribute to the apparent loss of basal NO-dependent vasodilation and thus to the increase in PAP that results from CIH [21].…”

“…The influence of intermittent hypoxia in pathological situations is detailed in three further papers by Martins et al [18], Correia et al [19]., and Prieto-Lloret et al [21] which provide new insights into the mechanisms of metabolic dysfunction, maladaptive mechanisms in the renal cortex and pulmonary hypertension in a rat model subjected to CIH, paving the way to new research questions, therapy options and precision medicine for OSA.…”

“…In turn, there is growing evidence that CIH may also compromise the pulmonary circulation, causing PH in both OSA patients and animal models. In this Special Issue, Prieto-Lloret et al [21] compare hemodynamics, vascular contractility, and L-arginine-NO metabolism in two rat models of PH, one associated with chronic sustained hypoxia (CSH) and the other with CIH exposure. They demonstrate that, while CSH and CIH cause several common effects, such as increased hematocrit, weight loss, and increased pulmonary arterial pressure (PAP), CSH appears to have a greater effect on the pulmonary circulation, whereas the effects of CIH are apparently more directed to the systemic circulation.…”