title: Vascular and parenchymal lesions along with enhanced neurogenesis characterize the brain of asymptomatic stroke-prone spontaneous hypertensive rats.
abstract: OBJECTIVE
  Spontaneously hypertensive stroke-prone rats (SHRSPs) develop hypertension, cerebrovascular abnormalities and a stroke phenotype in association with higher levels of proteinuria. Here, we focus on cerebral abnormalities preceding lesions detectable by MRI.
  
  
  METHODS
  Longitudinal assessment of brain histology was performed in salt-loaded male SHRSPs (n = 26) and Wistar-Kyoto (WKY) normotensive control animals (n = 27). Groups of rats were sacrificed at different time points: Time 0, before the salt diet administration; Time 1, when proteinuria achieved 40 mg/day; Time 2, when proteinuria exceeded 100 mg/day.
  
  
  RESULTS
  At Time 0, no brain lesions were observed. At Time 1, changes of the cortical penetrating arteries, vasogenic oedema, lacunae and focal cell loss appeared in SHRSPs and worsened at Time 2, although no lesions were yet detected by MRI. Staining for proliferation markers revealed a significant boost of cellular mitosis in the subventricular zone (SVZ) of SHRSPs. Moreover, we observed higher immunopositivity for nestin, glial fibrillary acidic protein and doublecortin (markers for neural stem cells, astrocytes and immature neurons, respectively). At Time 2, apoptotic caspase-3 as well as 4-hydroxynonenal-positive neurons were associated to decreased nestin and doublecortin staining. High expression levels of glial fibrillary acidic protein were maintained in the SVZ. No comparative alterations and SVZ activation were recorded in WKYs.
  
  
  CONCLUSIONS
  Appearance of vascular changes in SHRSPs, before any MRI-detectable brain lesion, is coupled to active neural proliferation in the SVZ. With disease progression, only newborn astrocytes can survive, likely because of the neurotoxicity triggered by brain oedema and oxidative stress.
authors.affiliation: Department of Neurology and Laboratory of Neuroscience, IRCCS Istituto Auxologico Italiano.
authors.forename: Lidia
authors.initials: L
authors.lastname: Cova
authors.forename: Paolo
authors.initials: P
authors.lastname: Gelosa
authors.forename: Elena
authors.initials: E
authors.lastname: Mura
authors.forename: Alessandro
authors.initials: A
authors.lastname: Mauro
authors.forename: Marco
authors.initials: M
authors.lastname: Stramba-Badiale
authors.forename: Georgios
authors.initials: G
authors.lastname: Michailidis
authors.forename: Alessandra
authors.initials: A
authors.lastname: Colonna
authors.forename: Nadia
authors.initials: N
authors.lastname: El Assawy
authors.forename: Alice
authors.initials: A
authors.lastname: Pignieri
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Busca
authors.forename: Elena
authors.initials: E
authors.lastname: Tremoli
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Silani
authors.forename: Luigi
authors.initials: L
authors.lastname: Sironi
authors.forename: Alberto
authors.initials: A
authors.lastname: Zanchetti
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000378:metabolism; D001921:Brain / Q000473:pathology; D001927:Brain Diseases / Q000503:physiopathology*; D049109:Cell Proliferation; D018450:Disease Progression; D000089622:Doublecortin Domain Proteins; D000089662:Doublecortin Protein; D004487:Edema / Q000473:pathology; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006973:Hypertension / Q000503:physiopathology; D007150:Immunohistochemistry; D008279:Magnetic Resonance Imaging; D008297:Male; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D058953:Neural Stem Cells / Q000378:metabolism; D055495:Neurogenesis; D009474:Neurons / Q000378:metabolism; D009479:Neuropeptides / Q000378:metabolism; D018384:Oxidative Stress; D011507:Proteinuria / Q000503:physiopathology; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D020521:Stroke / Q000503:physiopathology*; D013997:Time Factors
chemical_list: C000714848:Dcx protein, rat; D000089622:Doublecortin Domain Proteins; D000089662:Doublecortin Protein; D005904:Glial Fibrillary Acidic Protein; D008869:Microtubule-Associated Proteins; D009479:Neuropeptides