Blood–brain and blood–cerebrospinal fluid barrier permeability in spontaneously hypertensive rats

Abstract

BackgroundHypertension is an important risk factor for cerebrovascular disease, including stroke and dementia. Both in humans and animal models of hypertension, neuropathological features such as brain atrophy and oedema have been reported. We hypothesised that cerebrovascular damage resulting from chronic hypertension would manifest itself in a more permeable blood–brain barrier and blood–cerebrospinal fluid barrier. In addition, more leaky barriers could potentially contribute to an enhanced interstitial fluid and cerebrospinal fluid formation, which could, in turn, lead to an elevated intracranial pressure.MethodsTo study this, we monitored intracranial pressure and estimated the cerebrospinal fluid production rate in spontaneously hypertensive (SHR) and normotensive rats (Wistar Kyoto, WKY) at 10 months of age. Blood–brain barrier and blood–cerebrospinal fluid barrier integrity was determined by measuring the leakage of fluorescein from the circulation into the brain and cerebrospinal fluid compartment. Prior to sacrifice, a fluorescently labelled lectin was injected into the bloodstream to visualise the vasculature and subsequently study a number of specific vascular characteristics in six different brain regions.ResultsBlood and brain fluorescein levels were not different between the two strains. However, cerebrospinal fluid fluorescein levels were significantly lower in SHR. This could not be explained by a difference in cerebrospinal fluid turnover, as cerebrospinal fluid production rates were similar in SHR and WKY, but may relate to a larger ventricular volume in the hypertensive strain. Also, intracranial pressure was not different between SHR and WKY. Morphometric analysis of capillary volume fraction, number of branches, capillary diameter, and total length did not reveal differences between SHR and WKY.ConclusionIn conclusion, we found no evidence for blood–brain barrier or blood–cerebrospinal fluid barrier leakage to a small solute, fluorescein, in rats with established hypertension.Electronic supplementary materialThe online version of this article (10.1186/s12987-018-0112-7) contains supplementary material, which is available to authorized users.

Brain Morphometry and Longitudinal Relaxation Time of Spontaneously Hypertensive Rats (SHRs) in Early and Intermediate Stages of Hypertension Investigated by 3D VFA-SPGR MRI

“…Ventricular enlargement is a well-documented morphological feature of SHR rats and is an insignificant feature before 4 weeks of age but develops rather abruptly between 4 and 8 weeks of age and thereafter progresses, though at a slower rate, throughout adult life while maintaining normal intraventricular pressure, intracranial pressure and CSF production rate, all of which are consistent with our observation in morphological differences in SHR at two groups (Griswold WR et al, 1981;Naessens DMP et al, 2018;Ritter S, et al, 1988). Cerebral ventricular enlargement is also independent of elevated blood pressure because anti-hypertensive treatment by captopril treatment still resulted in the ventriculomegaly despite improvement in behavioral tests (Ritter S, et al, 1988;Wyss JM, et al, 1992).…”

Paravascular spaces: entry to or exit from the brain?

“…However, more recent work from our group showed that the BBB and blood-CSF barrier function of spontaneously hypertensive rats is still intact with respect to the permeability to small solutes, such as fluorescein (Naessens et al, 2018). It is possible that the BBB dysfunction is very subtle in hypertensive rats, initially affecting ions and water only.…”

“…We speculated that this could lead to increased ISF formation, a notion that was supported by increased spreading of tracers released into the hippocampus (Bedussi, Naessens, et al, ). However, more recent work from our group showed that the BBB and blood–CSF barrier function of spontaneously hypertensive rats is still intact with respect to the permeability to small solutes, such as fluorescein (Naessens et al., ). It is possible that the BBB dysfunction is very subtle in hypertensive rats, initially affecting ions and water only.…”

“…Pressure pulsations have been repeatedly suggested to drive paravascular flow (Iliff et al, 2013;Schley, Carare-Nnadi, Please, Perry, & Weller, 2006). We recently recorded relatively large pressure oscillations in the cisterna magna of rats induced by ventilation, and smaller oscillations induced by the heart beat (Naessens, de Vos, VanBavel, & Bakker, 2018). However, a fundamental problem with this hypothesis is that oscillations in vascular diameter that result from these pressure fluctuations require a valve in the paravascular space to generate bulk flow in this compartment.…”

Alteration in the Function and Expression of SLC and ABC Transporters in the Neurovascular Unit in Alzheimer’s Disease and the Clinical Significance

“…Central nervous system (CNS) barriers are vital to the brain microenvironment for the regulation of neuronal functions, including nutrient transport and protection of the brain from toxins [1]. Brain barriers include the bloodbrain barrier (BBB) and blood-cerebrospinal fluid (CSF) barrier (BCSFB) [2]. BBB, a semipermeable border, is composed of brain microvascular endothelial cells that are sheathed by pericytes, perivascular astrocytic end-feet, neurons and microglia, which constitute a functional unit, namely, the neurovascular unit (NVU).…”