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.
Highlights
Conditions during early life can significantly impact adult health and disease, the cardiovascular system
We have previously shown that O2 exposure of newborn rats, a well-established model of prematurity-related O2 injury, leads in early adulthood to elevated blood pressure, endothelial dysfunction with enhanced superoxide production, and increased pulse wave velocity [19,20,21]
Collagen and elastin content To determine whether transient neonatal oxygen exposure induced aortic wall structure changes that could be present prior to blood pressure increase and vascular dysfunction present in adults [19], we assessed smooth muscle cells, and collagen and elastin content at 4 weeks of age
Summary
Conditions during early life (pre- and early postnatal) can significantly impact adult health and disease, the cardiovascular system. Stiffening of large central arteries, the aorta, occurs during physiological as well as pathological processes such as aging and hypertension [4]. Elastin synthesis in the vessels peaks in late fetal life in humans [7] (and in the first postnatal days in rodents), decreases rapidly after birth and is minimal in the adult aorta. Elastin content of the aortic wall and other large conduit arteries is determined relatively early during development, with a low capacity for synthesis thereafter; modification due to adverse conditions during the perinatal period could have long lasting consequences. Collagen synthesis increases during intrauterine life and persists after birth; the proportion of collagen in vessels increases with age and synthesis can be accelerated in pathological conditions such as hypertension [9]
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