Abstract
Increased activity of the sympathetic nervous system has been highlighted as a key factor that contributes to the development and maintenance of arterial hypertension. However, the factors that precipitate sustained increases in sympathetic activity remain poorly understood. Resting tissue oxygen partial pressure (PtO2) in the brainstem of anesthetized spontaneously hypertensive rats (SHRs) has been shown to be lower than in normotensive rats despite normal levels of arterial PO2. A hypoxic environment in the brainstem has been postulated to activate astroglial signalling mechanisms in the rostral ventrolateral medulla (RVLM) which in turn increase the excitability of presympathetic neuronal networks. In this study, we assessed the expression of indirect markers of tissue hypoxia and astroglial cell activation in the RVLM of SHRs and age-matched normotensive Wistar rats. Immunohistochemical labelling for hypoxia-induced factor-1α (HIF-1α) and bound pimonidazole adducts revealed the presence of tissue hypoxia in the RVLM of SHRs. Double immunostaining showed co-localization of bound pimonidazole labelling in putative presympathetic C1 neurons and in astroglial cells. Quantification of glial fibrillary acidic protein (GFAP) immunofluorescence showed relatively higher number of astrocytes and increased GFAP mean grey value density, whilst semi-quantitative analysis of skeletonized GFAP-immunoreactive processes revealed greater % area covered by astrocytic processes in the RVLM of adult SHRs. In conclusion, the morphological findings of tissue hypoxia and astrogliosis within brainstem presympathetic neuronal networks in the SHR support previous observations, showing that low brainstem PtO2 and increased astroglial signalling in the RVLM play an important role in pathological sympathoexcitation associated with the development of arterial hypertension.
Highlights
There is mounting evidence that increased sympathetic nervous system (SNS) activation is intricately linked to the development and maintenance of arterial hypertension, the causative role is still controversial
Abundant hypoxic cells were identified in the C1 region of naïve spontaneously hypertensive rats (SHRs) and to a much lesser extent in Wistar rats immunolabelled for hypoxia-induced factor-1α (HIF-1α)
We found greater numbers of HIF-1α-immunoreactive (-ir) cells in the C1 region of SHRs compared to Wistar rats (276.4 749.8 cells in SHRs vs 53.1 723.3 cells in Wistar rats, p o0.001, n1⁄4 5; Fig. 1)
Summary
There is mounting evidence that increased sympathetic nervous system (SNS) activation is intricately linked to the development and maintenance of arterial hypertension, the causative role is still controversial. Human studies have shown elevated plasma noradrenaline and increased vasoconstrictor sympathetic activity in individual organs such as the kidneys, heart and skeletal muscle in hypertensive patients There is evidence that neurovascular coupling responses triggered by neuronal stimulation are significantly impaired in the brain of hypertensive subjects (Jennings et al, 2005; Calcinaghi et al, 2013; Iddings et al, 2001).
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