The importance of the sympathetic nervous system (SNS) in initiation and/or maintenance of arterial hypertension has been considered for decades. In fact, surgical lumbar sympathectomy and splanchnic nerve resection were employed as one of the pioneering treatments for hypertension in humans [1, 2]. However, an argument against the participation of the SNS in the long-term maintenance of hypertension is the hypothesis that an increase in sympathetic vasomotor activity by itself, cannot cause persistent hypertension without a chronic and sustained change in renal function [3]. More recently, however, the importance of SNS in hypertension in humans has been highlighted in the studies testing selective catheter-based renal sympathetic nerve ablation in patients with resistant hypertension, indicating that chronic activation of the renal nerves (whether afferent and/or efferent) is a major mechanism to trigger and maintain systemic hypertension [4]. It is well known that chronic activation of renal sympathetic nerve activity (RSNA) is able to change the renal function by increasing the renin secretion, the sodium reabsorption and inducing renal vasoconstriction, contributing to hypertension [5, 6]. The mechanisms underlying the initiation and maintenance of RSNA activation in hypertension are not fully understood, although it has been described that a complex interaction among the renin-angiotensin system (RAS), the SNS and oxidative stress in the brain and in the kidneys plays a major role [7,8,9]. Interestingly, augmented RSNA and hypertension have been reported in offspring of diabetic mothers [10]and maternal obesity [11] indicating that adverse conditions during the fetal development may trigger RSNA activation leading to the development of hypertension. Hao et al. [12] had previously reported that prenatal exposure to lipopolysaccharide (LPS) resulted in higher renal cortex renin mRNA expression and hypertension in offspring rats. The present study from Hao et al. [13] described that exposure to LPS in pregnant rats increased RAS activity and oxidative stress in the paraventricular nucleus of hypothalamus (PVN), accompanied by RSNA activation and hypertension in offsprings, indicating that inflammation during the fetal development is involved in the onset of hypertension in the adult life. It has been previously reported that the interaction between RSNA and intrarenal RAS may alter the renal function leading to changes in sodium reabsorption and hypertension [14].

In addition, the study from Hao et al. [13] showed that Melatonin treatment associated with LPS administration in the pregnant mothers reduced RAS activity and oxidative stress in the PVN, reduced RSNA and blood pressure and increased urine sodium excretion in offspring. Thus, the study from Hao et al. [13] supports previous evidence that inflammation and oxidative damage within the brain is a key mechanism driving RSNA activation, renal dysfunction and hypertension [15, 16]. In pregnant rats, exposure to LPS can increase the permeability of the placental barrier, allowing inflammatory cytokines to reach the fetus [17]. Thus, maternal and fetal exacerbated immune responses may potentially contribute to the dysfunction of brain regions related to the control of RSNA and blood pressure in the offspring [18]. In this sense, inflammation, Ang II and other signals are believed to activate microglia - the resident immune cells - in the PVN, enhancing neuroinflammation, and RSNA. Evidence that supports this hypothesis is based on previous studies that described microglia activation in the PVN in an Ang II-induced model of hypertension in rats, leading to increased cell proliferation and pro-inflammatory cytokines in the brain [19, 20]. One possible pathway by which the circulating cytokines activate the PVN neurons is through the Subfornical organ (SFO), a brain region outside the blood-brain-barrier that is crucial in sensing and responding to peripheral cytokines (Fig. 1). The SFO sends projections to the PVN and it was described that administration of TNF-α or IL-1β in the SFO induces an increase in RSNA and hypertension in rats [21]. The underlying mechanisms of this pathway involve the activation of microglial and consequently increase in expression of cytokine receptors in the SFO and PVN. In addition, angiotensinogen released from microglia may increase local Ang II formation, oxidative stress and consequently, the firing rate of PVN neurons (Fig. 1). Accordingly, a study showed that selective denervation of renal afferents changed GABAergic inputs and decreased microglia activation in the PVN in a model of renovascular hypertension characterized by increased brain RAS activation and oxidative damage [22]. The study from Hao et al. [13] describes that the PVN neurons firing rate is significantly increased in offspring of mothers treated with LPS. Interestingly, this effect was blunted by Melatonin treatment, indicating that the oxidative stress is a major mechanism driving PVN neurons. Therefore, neuroinflammation and oxidative stress in the brain, mainly mediated by resident microglia in the PVN, during pregnancy emerge as crucial components in the development of hypertension in offspring and potential targets for prevention and treatment of postnatal pathophysiological conditions associated with increased SNS activity, such as arterial hypertension and chronic cardiovascular diseases. However, further studies are necessary to elucidate the involvement of microglia, and its polarization phenotype, and/or changes in epigenetic factors.

Fig. 1
figure 1

Possible neural pathways involved in the RSNA activation in response to maternal exposure to lipopolysaccharide (LPS). The subfornical organ (SFO) located outside of the blood-brain barrier responds to circulating cytokines. The release of cytokines and angiotensinogen by microglia in the region of the paraventricular nucleus of the hypothalamus (PVN) increases local formation of angiotensin II (Ang II), oxidative stress (ROS) and the activity of PVN neurons in the offspring. RVLM Rostroventrolateral Medulla, IML intermediolateral column, RSNA renal sympathetic nerve activity. “Created with BioRender.com”

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