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Vascular and parenchymal lesions along with enhanced neurogenesis characterize the brain of asymptomatic stroke-prone spontaneous hypertensive rats

Cova, Lidiaa,*; Gelosa, Paolob,*; Mura, Elenac,*; Mauro, Alessandroc,d; Stramba-Badiale, Marcoe; Michailidis, Georgiose; Colonna, Alessandrac; El Assawy, Nadiac; Pignieri, Aliceb; Busca, Giuseppef; Tremoli, Elenab,g; Silani, Vincenzoa,h; Sironi, Luigib,g,*; Zanchetti, Albertoi

doi: 10.1097/HJH.0b013e3283619d7f

Background and objectives: 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.

Conclusion: 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.

aDepartment of Neurology and Laboratory of Neuroscience, IRCCS Istituto Auxologico Italiano

bDepartment of Pharmacological and Biomolecular Sciences, University of Milan, Milan

cLaboratory of Neurobiology, Istituto Auxologico Italiano, S. Giuseppe Hospital, Piancavallo di Oggebbio (VB)

dDepartment of Neuroscience, University of Turin, Turin

eDepartment of Geriatrics and Cardiovascular Medicine, IRCCS Istituto Auxologico Italiano

fDepartment of Clinical Sciences and Community Health, University of Milan, Cardiovascular Medicine, Fondazione IRCCS Cà Granda, Ospedale Maggiore Policlinico

gIRCCS Centro Cardiologico Monzino

hDepartment of Pathophysiology and Transplantation, ‘Dino Ferrari’ Centre, University of Milan

iIRCCS Istituto Auxologico Italiano and University of Milan, Milan, Italy

*Lidia Cova, Paolo Gelosa, Elena Mura, and Luigi Sironi contributed equally to the study reported in this article.

Correspondence to Alberto Zanchetti, MD, Istituto Auxologico Italiano, Via L. Ariosto 13, 20145 Milan, Italy. Tel: +39 02 619112237; fax: +39 02 619112294; e-mail:

Abbreviations: DCX, doublecortin; 4-HNE, 4-hydroxynonenal; GFAP, glial fibrillary acidic protein; MRI, magnetic resonance imaging; PCNA, proliferating cell nuclear antigen; SBP, systolic arterial blood pressure; SHRSP, spontaneously hypertensive stroke-prone rat; SVD, small vessel disease; SVZ, subventricular zone; TUNEL, terminal deoxynucleotidyl transferase dUTP neck end labelling; VAF, vanadium acid fuxin; WKY, Wistar–Kyoto rat

Received 1 February, 2013

Revised 4 March, 2013

Accepted 25 March, 2013

© 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins