Abstract
BackgroundThe function of pericytes remains questionable but with improved cultured technique and the use of genetically modified animals, it has become increasingly clear that pericytes are an integral part of blood–brain barrier (BBB) function, and the involvement of pericyte dysfunction in certain cerebrovascular diseases is now emerging. The porcine stress syndrome (PSS) is the only confirmed, homologous model of malignant hyperthermia (MH) in veterinary medicine. Affected animals can experience upon slaughter a range of symptoms, including skeletal muscle rigidity, metabolic acidosis, tachycardia and fever, similar to the human syndrome. Symptoms are due to an enhanced calcium release from intracellular stores. These conditions are associated with a point mutation in ryr1/hal gene, encoding the ryanodine receptor, a calcium channel. Important blood vessel wall muscle modifications have been described in PSS, but potential brain vessel changes have never been documented in this syndrome.MethodsIn the present work, histological and ultrastructural analyses of brain capillaries from wild type and ryr1 mutated pigs were conducted to investigate the potential impairment of pericytes, in this pathology. In addition, brain pericytes were isolated from the three porcine genotypes (wild-type NN pigs; Nn and nn pigs, bearing one or two (n) mutant ryr1/hal alleles, respectively), and tested in vitro for their influence on the permeability of BBB endothelial monolayers.ResultsEnlarged perivascular spaces were observed in ryr1-mutant samples, corresponding to a partial or total detachment of the astrocytic endfeet. These spaces were electron lucent and sometimes filled with lipid deposits and swollen astrocytic feet. At the ultrastructural level, brain pericytes did not seem to be affected because they showed regular morphology and characteristics, so we aimed to check their ability to maintain BBB properties in vitro. Our results indicated that pericytes from the three genotypes of pigs had differing influences on the BBB. Unlike pericytes from NN pigs, pericytes from Nn and nn pigs were not able to maintain low BBB permeability.ConclusionsElectron microscopy observations demonstrated brain capillary modifications in PSS condition, but no change in pericyte morphology. Results from in vitro experiments suggest that brain pericytes from ryr1 mutated pigs, even if they are not affected by this condition at the ultrastructural level, are not able to maintain BBB integrity in comparison with pericytes from wild-type animals.
Highlights
The function of pericytes remains questionable but with improved cultured technique and the use of genetically modified animals, it has become increasingly clear that pericytes are an integral part of blood–brain barrier (BBB) function, and the involvement of pericyte dysfunction in certain cerebrovascular diseases is emerging
Brain capillaries are the anatomical basis of the blood–brain barrier (BBB), which is the focal point of the neurovascular unit (NVU) comprising endothelial cells and pericytes at the capillary level, and astrocytes, oligodendrocytes, microglia and neurons
Our results indicated that the greater Lucifer yellow (LY) permeability observed with pericytes from mutant pigs could not be accounted for by vascular endothelial growth factor (VEGF)-A secretion, since levels of this factor were higher in the NN control condition than in mutant pericyte-endothelial cell cocultures
Summary
The function of pericytes remains questionable but with improved cultured technique and the use of genetically modified animals, it has become increasingly clear that pericytes are an integral part of blood–brain barrier (BBB) function, and the involvement of pericyte dysfunction in certain cerebrovascular diseases is emerging. Pigs carrying the halothane sensitivity (n) allele at the ryr locus can exhibit rapid-onset, severe malignant hyperthermia (MH), experiencing a range of symptoms, including skeletal muscle rigidity, metabolic acidosis, tachycardia and fever, which are due to an enhanced calcium release from intracellular stores. This condition has been studied because these animals typically produce pale, soft and exsudative pork, which is responsible for a poor meat quality and has huge consequences in meat processing industry. This dysfunction is associated with neurologic diseases such as stroke and has been suggested in Alzheimer’s disease [5]
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