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Transgenic mice constitutively overexpressing the cytokine transforming growth factor-[beta]1 (TGF-[beta]1) (TGF mice) display cerebrovascular alterations as seen in Alzheimer's disease (AD) and vascular cognitive impairment and dementia (VCID), but no or only subtle cognitive deficits. TGF-[beta]1 may exert part of its deleterious effects through interactions with angiotensin II (AngII) type 1 receptor (AT1R) signaling pathways. We test such interactions in the brain and cerebral vessels of TGF mice by measuring cerebrovascular reactivity, levels of protein markers of vascular fibrosis, nitric oxide synthase activity, astrogliosis, and mnemonic performance in mice treated (6 months) with the AT1R blocker losartan (10 mg/kg per day) or the angiotensin converting enzyme inhibitor enalapril (3 mg/kg per day). Both treatments restored the severely impaired cerebrovascular reactivity to acetylcholine, calcitonin gene-related peptide, endothelin-1, and the baseline availability of nitric oxide in aged TGF mice. Losartan, but not enalapril, significantly reduced astrogliosis and cerebrovascular levels of profibrotic protein connective tissue growth factor while raising levels of antifibrotic enzyme matrix metallopeptidase-9. Memory was unaffected by aging and treatments. The results suggest a pivotal role for AngII in TGF-p1-induced cerebrovascular dysfunction and neuroinflammation through AT1R-mediated mechanisms. Further, they suggest that AngII blockers could be appropriate against vasculopathies and astrogliosis associated with AD and VCID. Key words: losartan, enalapril, cerebrovascular reactivity, astrogliosis, TGF-[beta]1, AT1 receptors. Les souris transgeniques qui surexpriment constitutivement la cytokine << transforming growth factor-[beta]1 >> (TGF- [beta]1), denommees souris TGF, presentent des modifications vasculaires cerebrales semblables a celles observees dans la maladie d'Alzheimer (MA) et l'atteinte cognitive et la demence vasculaires (ACDV), mais avec peu ou pas de deficits cognitifs. Le TGF-[beta]1 pourrait exercer une partie de ses effets deleteres par des interactions avec les voies de signalisation du recepteur de type 1 (AT1R) de l'angiotensine II (AngII). Nous avons teste de telles interactions dans le cerveau et les vaisseaux cerebraux de souris TGF en mesurant la reactivite vasculaire cerebrale, les taux proteiques de marqueurs de la fibrose vasculaire et de la NO synthase, l'astrogliose et les performances mnemoniques chez des souris traitees pendant 6 mois avec le losartan (bloqueur des AT1R; 10 mg/kg par jour) ou de l'enalapril (inhibiteur de l'enzyme de conversion de l'angiotensine; 3 mg/kg par jour). Chez les souris TGF agees, les deux traitements ont retabli la reactivite gravement reduite des vaisseaux cerebraux a l'acetylcholine, au peptide relie au gene calcitonine, a l'endotheline-1, ainsi que la disponibilite de l'oxyde nitrique. Le losartan, mais pas l'enalapril, a permis de reduire l'astrogliose et les taux vasculaires cerebraux du facteur de croissance des proteines du tissu conjonctif tout en augmentant les taux de metallopeptidase 9 matricielle (une enzyme antifibrotique). La memoire des souris n'etait affectee ni par le vieillissement, ni par les traitements. Ces resultats suggerent un role central de l'AngII dans l'atteinte vasculaire cerebrale et la neuro-inflammation induites par le TGF-[beta]1 via des mecanismes impliquant l'activation des AT1R. De plus, ces resultats laissent entendre que les bloqueurs de l'AngII pourraient constituer des agents prometteurs contre les pathologies vasculaires et l'astrogliose associees a la MA et l'ACDV. Mots-cles : losartan, enalapril, reactivite vasculaire cerebrale, astrogliose, TGF-[beta]1, recepteurs AT1., Introduction Evidence suggests that the renin-angiotensin system (RAS) is altered in Alzheimer's disease (AD) and vascular cognitive impairment and dementia (VCID) patients (Kehoe 2009), and that angiotensin receptor blockers can [...]

A[T.sub.2] receptors may act in opposition to and in balance with A[T.sub.1] receptors, their stimulation having beneficial effects. We found renal A[T.sub.2] receptor expression in female mice higher than in male mice. We asked the question of whether such expression might be estrogen dependent. In male, female, ovariectomized, and estrogentreated ovariectomized mice, we studied renal A[T.sub.1] and A[T.sub.2] receptors by immunocytochemistry and autoradiography, A[T.sub.2] receptor mRNA by RT-PCR, and cAMP, cGMP, and PG[E.sub.2] by RIA. A[T.sub.1] receptors predominated. A[T.sub.2] receptors were present in glomeruli, medullary rays, and inner medulla, and in female kidney capsule. A[T.sub.1] and A[T.sub.2] receptors colocalized in glomeruli. Female mice expressed fewer glomerular A[T.sub.1] receptors. Ovariectomy decreased A[T.sub.1] receptors in medullary rays and capsular A[T.sub.2] receptors. Estrogen administration normalized A[T.sub.1] receptors in medullary rays and increased A[T.sub.2] receptors predominantly in capsule and inner medulla, and also in glomeruli, medullary rays, and inner stripe of outer medulla. In medullas of estrogen-treated ovariectomized mice there was higher A[T.sub.2] receptor mRNA, decreased cGMP, and increased PG[E.sub.2] content. We propose that the protective effects of estrogen may be partially mediated through enhancement of A[T.sub.2] receptor stimulation. renin-angiotensin system; reproductive hormones; kidney function; cyclic nucleotides; prostaglandins

Angiotensin II is one of over 36 peptides that have been found to play a part in nervous function. Studies show that there may be an angiotensin system in the brain which could have a role in neural functions such as thirst, salt appetite and cognition. The part that angiotensin II plays in the renin-angiotensin system is unclear, but it may aid in development and differentiation.

BACKGROUND The right atrium is densely innervated and provides sensory input to important cardiocirculatory reflexes controlling cardiac output and blood pressure. Its angiotensin (Ang) II-expressing innervation may release Ang II as a neuropeptide cotransmitter to modulate reflexes but has not yet been characterized. METHODS Intraoperative surgical biopsies from human right atria (n = 7) were immunocytologically stained for Ang II, tyrosine hydroxylase (TH), and synaptophysin (SYN). Tissue angiotensins were extracted and quantified by radioimmunoassay. RESULTS Angiotensinergic fibers were frequent in epicardial nerves and around vessels with variable TH co-localization (none to >50%/bundle). Fibers were also widely distributed between cardiomyocytes and in the endocardium where they were typically nonvaricose, TH/SYN-negative and usually accompanied by varicose catecholaminergic fibers. In the endocardium, some showed large varicosities and were partially TH or SYN-positive. A few endocardial regions showed scattered nonvaricose Ang fibers ending directly between endothelial cells. Occasional clusters of thin varicose terminals co-localizing SYN or TH were located underneath, or protruded into, the endothelium. Endocardial density of Ang and TH-positive fibers was 30-300 vs. 200-450/mm2. Atrial Ang II, III, and I concentrations were 67, 16, and 5 fmol/g (median) while Ang IV and V were mostly undetectable. CONCLUSIONS The human right atrium harbors an abundant angiotensinergic innervation and a novel potential source of atrial Ang II. Most peripheral fibers were noncatecholaminergic afferents or preterminal vagal efferents and a minority was presumably sympathetic. Neuronal Ang II release from these fibers may modulate cardiac and circulatory reflexes independently from plasma and tissue Ang II sources. [ABSTRACT FROM AUTHOR]