Remodeling of Aorta Extracellular Matrix as a Result of Transient High Oxygen Exposure in Newborn Rats: Implication for Arterial Rigidity and Hypertension Risk

Abstract

Neonatal high-oxygen exposure leads to elevated blood pressure, microvascular rarefaction, vascular dysfunction and arterial (aorta) rigidity in adult rats. Whether structural changes are present in the matrix of aorta wall is unknown. Considering that elastin synthesis peaks in late fetal life in humans, and early postnatal life in rodents, we postulated that transient neonatal high-oxygen exposure can trigger premature vascular remodelling. Sprague Dawley rat pups were exposed from days 3 to 10 after birth to 80% oxygen (vs. room air control) and were studied at 4 weeks. Blood pressure and vasomotor response of the aorta to angiotensin II and to the acetylcholine analogue carbachol were not different between groups. Vascular superoxide anion production was similar between groups. There was no difference between groups in aortic cross sectional area, smooth muscle cell number or media/lumen ratio. In oxygen-exposed rats, aorta elastin/collagen content ratio was significantly decreased, the expression of elastinolytic cathepsin S was increased whereas collagenolytic cathepsin K was decreased. By immunofluorescence we observed an increase in MMP-2 and TIMP-1 staining in aortas of oxygen-exposed rats whereas TIMP-2 staining was reduced, indicating a shift in the balance towards degradation of the extra-cellular matrix and increased deposition of collagen. There was no significant difference in MMP-2 activity between groups as determined by gelatin zymography. Overall, these findings indicate that transient neonatal high oxygen exposure leads to vascular wall alterations (decreased elastin/collagen ratio and a shift in the balance towards increased deposition of collagen) which are associated with increased rigidity. Importantly, these changes are present prior to the elevation of blood pressure and vascular dysfunction in this model, and may therefore be contributory.

Long‐Term Effects of Neonatal Hyperoxia in Adult Mice

“…This finding in addition to the thicker walls may increase the stiffness of the aortic wall predisposing to hypertension. Remodeling of the aortic extracellular matrix noted four weeks following hyperoxia exposure is associated with an altered elastin to collagen ratio in mice (Huyard et al, ). These changes could be present prior to elevation of blood pressure and vascular dysfunction and hence may contribute to the development of hypertension.…”

Aortic Elastic Properties in Preschool Children Born Preterm

“…On top of that, hyperoxic stress caused by transient neonatal highoxygen exposure in rats (a model of preterm birth-related complications) was shown to accelerate elastin precursor degradation and unfavorably affect matrix composition. 45 Finally, premature birth disrupts elastin synthesis, usually peaking in a narrow time window at the end of gestation. After birth, elastogenesis pursues but decreases rapidly when the transitional rise in blood pressure stabilizes.…”

Endothelial colony-forming cell therapy for heart morphological changes after neonatal high oxygen exposure in rats, a model of complications of prematurity

“…Perivascular fibrosis of the aorta was also reported in this model (Huyard et al. 2014). Myocardial fibrosis, and particularly perivascular fibrosis, is increasingly recognized a key driver in the development of cardiac dysfunction, and there are few effective antifibrosis therapies (Ytrehus et al.…”