Biomechanical and structural responses of the aorta to intermittent hypobaric hypoxia in a rat model

Abstract

High altitude hypoxia is a condition experienced by diverse populations worldwide. In addition, several jobs require working shifts where workers are exposed to repetitive cycles of hypobaric hypoxia and normobaric normoxia. Currently, few is known about the biomechanical cardiovascular responses of this condition. In the present study, we investigate the cycle-dependent biomechanical effects of intermittent hypobaric hypoxia (IHH) on the thoracic aorta artery, in terms of both structure and function. To determine the vascular effects of IHH, functional, mechanical and histological approaches were carried out in the thoracic aorta artery, using uniaxial, pre-stretch, ring opening, myography, and histological tests. Three groups of rats were established: control (normobaric normoxia, NN), 4-cycles of intermittent hypoxia (short-term intermittent hypobaric hypoxia, STH), and 10-cycles of intermittent hypoxia (long-term intermittent hypobaric hypoxia, LTH). The pre-stretch and ring opening tests, aimed at quantifying residual strains of the tissues in longitudinal and circumferential directions, showed that the hypoxia condition leads to an increase in the longitudinal stretch and a marked decrease of the circumferential residual strain. The uniaxial mechanical tests were used to determine the elastic properties of the tissues, showing that a general stiffening process occurs during the early stages of the IH (STH group), specially leading to a significative increase in the high strain elastic modulus ($$E_{2}$$ E 2 ) and an increasing trend of low strain elastic modulus ($$E_{1}$$ E 1 ). In contrast, the LTH group showed a more control-like mechanical behavior. Myography test, used to assess the vasoactive function, revealed that IH induces a high sensitivity to vasoconstrictor agents as a function of hypoxic cycles. In addition, the aorta showed an increased muscle-dependent vasorelaxation on the LTH group. Histological tests, used to quantify the elastic fiber, nuclei, and geometrical properties, showed that the STH group presents a state of vascular fibrosis, with a significant increase in elastin content, and a tendency towards an increase in collagen fibers. In addition, advanced stages of IH (LTH), showed a vascular remodeling effect with a significant increase of internal and external diameters. Considering all the multidimensional vascular effects, we propose the existence of a long-term passive adaptation mechanism and vascular dysfunction as cycle-dependent effects of intermittent exposures to hypobaric hypoxia.

Inhibition of Vascular Endothelial Cadherin Cleavage Prevents Elastic Fiber Alterations and Atherosclerosis Induced by Intermittent Hypoxia in the Mouse Aorta

“…In C57BL/6J mice, IH generated the already known vascular remodeling (i.e., increased IMT) [12] and elastic fiber/lamella alteration [10,18,36] effects, which were prevented or inhibited by acriflavine, pazopanib and saracatinib, thereby suggesting the involvement of VE-cadherin-related endothelial permeability. This also opens a new possibility of a mechanistic explanation for the already demonstrated IH-induced arterial stiffening [7][8][9]11].…”

“…The link between OSAS/IH and the structural and functional impairment of vascular endothelium has been well established in both patients and animal models. Indeed, IH induces various mechanisms, such as elevation of oxidative stress, activation of Hypoxia-Inducible Factor-1 (HIF-1) and its target genes, such as VEGF [5,6], low grade chronic inflammation and sympathetic activation that, in turn, lead to endothelial dysfunction, hypertension, vascular wall thickening and degradation of the elastic fibers [7][8][9][10][11] and atherosclerosis [3,12,13].…”

A study on the ultimate mechanical properties of middle-aged and elderly human aorta based on uniaxial tensile test

“…In the first, alterations in elastic fibers predominate when subjected to physiological stresses. During the transition stage, the slope gradually increases as collagen fibers engage in the activity, indicating hyperelasticity ( Li et al, 2023 ; Wang et al, 2023 ); during the reinforcing stage, the slope reaches its maximum and the collagen fibers provide their greatest effect; during the failure stage, the sample completely shreds as the ultimate load is met ( Utrera et al, 2022 ).…”

Biomechanical effects of hemin and sildenafil treatments on the aortic wall of chronic-hypoxic lambs

“…The biomechanical tests performed in this study were carried out according to protocols and procedures detailed in Navarrete et al (2020) , Rivera et al (2020) , and Utrera et al (2022) . The tests are briefly described below.…”

“… Drexler et al (2008) reported stiffening on extrapulmonary arteries (trunk, right, and left main arteries) of rats with pulmonary hypertension induced by high altitude (5,000 m). In a recent experimental study, Utrera et al (2022) described mechanical and structural alterations on descending thoracic aortas of rats as a cycle-dependent effect of the exposure to intermittent HAHH.…”