The most important acute neurological diseases seen at neurosurgery departments are traumatic brain injuries (TBI) and subarachnoid hemorrhages (SAH). In both diseases the pathophysiological sequela are complex and have not been fully understood up to now, and rodent models using rats and mice are most suitable for the investigation of the pathophysiological details. In both models, surgery is performed under anesthesia, followed by assessment of their functional outcome and behavioral testing before brain tissue analysis after euthanasia. Postoperative analgesia is mandatory, and supplementary care is highly recommended for refinement purposes. Pain and stress assessment is mainly based on clinical and behavioral signs, and further research is needed to improve the evaluation of severity in these models.

BACKGROUND: Whether aortic valve stenosis (AS) can adversely affect systemic endothelial function independently of standard modifiable cardiovascular risk factors is unknown. METHODS: We therefore investigated endothelial and cardiac function in an experimental model of AS mice devoid of standard modifiable cardiovascular risk factors and human cohorts with AS scheduled for transcatheter aortic valve replacement. Endothelial function was determined by flow-mediated dilation using ultrasound. Extracellular hemoglobin (eHb) concentrations and nitric oxide (NO) consumption were determined in blood plasma of mice and humans by ELISA and chemiluminescence. This was complemented by measurements of aortic blood flow using 4-dimensional flow acquisition by magnetic resonance imaging and computational fluid dynamics simulations. The effects of plasma and red blood cell (RBC) suspensions on vascular function were determined in transfer experiments in a murine vasorelaxation bioassay system. RESULTS: In mice, the induction of AS caused systemic endothelial dysfunction. In the presence of normal systolic left ventricular function and mild hypertrophy, the increase in the transvalvular gradient was associated with elevated eryptosis, increased eHb, and increased plasma NO consumption; eHb sequestration by haptoglobin restored endothelial function. Because the aortic valve orifice area in patients with AS decreased, postvalvular mechanical stress in the central ascending aorta increased. This was associated with elevated eHb, circulating RBC-derived microvesicles, eryptotic cells, lower haptoglobin levels without clinically relevant anemia, and consecutive endothelial dysfunction. Transfer experiments demonstrated that reduction of eHb by treatment with haptoglobin or elimination of fluid dynamic stress by transcatheter aortic valve replacement restored endothelial function. In patients with AS and subclinical RBC fragmentation, the remaining circulating RBCs before and after transcatheter aortic valve replacement exhibited intact membrane function, deformability, and resistance to osmotic and hypoxic stress. CONCLUSIONS: AS increases postvalvular swirling blood flow in the central ascending aorta, triggering RBC fragmentation with the accumulation of hemoglobin in the plasma. This increases NO consumption in blood, thereby limiting vascular NO bioavailability. Thus, AS itself promotes systemic endothelial dysfunction independent of other established risk factors. Transcatheter aortic valve replacement is capable of limiting NO scavenging and rescuing endothelial function by realigning postvalvular blood flow to near physiological patterns. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifiers: NCT05603520 and NCT01805739.

Cerebral vasospasm (CVS) following a subarachnoid hemorrhage (SAH) is a critical complication driven by imbalances between vasodilators and vasoconstrictors. This review explores the bidirectional interplay between nitric oxide (NO) and endothelin-1 (ET-1) in CVS pathogenesis. NO, a potent vasodilator mainly produced by endothelial and neuronal nitric oxide synthase (eNOS/nNOS) under normal physiological conditions, is scavenged early after SAH by hemoglobin derivatives, leading to microcirculatory dysfunction, pericyte constriction, and impaired neurovascular coupling. Conversely, ET-1 exacerbates vasoconstriction by suppressing NO synthesis via ROS-dependent eNOS uncoupling and Rho-kinase activation. The NO/ET-1 axis further influences delayed cerebral ischemia (DCI) through mechanisms like 20-HETE-mediated cGMP suppression and oxidative stress. Emerging therapies—including NO donors, NOS gene therapy, and ET-1 receptor antagonists—aim to restore this balance. Understanding these pathways offers translational potential for mitigating CVS and improving outcomes post-SAH.

Intravenously administered perfluorocarbon nanoemulsions (PFCs) are taken up by phagocytic immune cells, which enables the noninvasive visualization of inflammatory hot spots by combined 1H/19F magnetic resonance imaging. However, little is known about the influence of inflammatory stimuli on cellular uptake and biodistribution of PFCs. Here, we systematically investigated the impact of inflammation induced by subcutaneous implantation of Matrigel/lipopolysaccharide or myocardial infarction (50 min ischemia reperfusion) on PFC uptake and biodistribution in C57BL/6J mice. We detected strong 19F signals in Matrigel/lipopolysaccharide plugs and infarcted hearts, which were completely absent in controls. Cellular uptake of PFCs was increased in neutrophils isolated from the blood and Matrigel/lipopolysaccharide plugs, whereas uptake by monocytes was only slightly elevated. In contrast, myocardial infarction caused only a moderate early increase of PFC uptake in monocytes and neutrophils. Interestingly, the inflammatory model did also affect the biodistribution of the PFCs. The blood half-life of PFCs was slightly increased after Matrigel/lipopolysaccharide implantation, whereas it was reduced after myocardial infarction. Compared to controls, the 19F signal of the liver was significantly stronger in Matrigel/lipopolysaccharide but not in myocardial infarction animals. Interestingly, stimulation of primary immune cells and RAW264.7 macrophages with lipopolysaccharide had no effect on PFC uptake, whereas C-reactive protein incubation elevated internalization of PFCs at least in RAW264.7 cells. In conclusion, we show that the cellular PFC uptake can differ between individual inflammatory conditions. This is an important aspect that has to be considered for the proper interpretation of 1H/19F magnetic resonance imaging data obtained from inflammatory hot spots.