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. 2013 Nov;33(11):1732-42.
doi: 10.1038/jcbfm.2013.143. Epub 2013 Aug 14.

Age-related autoregulatory dysfunction and cerebromicrovascular injury in mice with angiotensin II-induced hypertension

Peter Toth  1 , Zsuzsanna Tucsek, Danuta Sosnowska, Tripti Gautam, Matthew Mitschelen, Stefano Tarantini, Ferenc Deak, Akos Koller, William E Sonntag, Anna Csiszar, Zoltan Ungvari
Affiliations

Age-related autoregulatory dysfunction and cerebromicrovascular injury in mice with angiotensin II-induced hypertension

Peter Toth et al. J Cereb Blood Flow Metab. 2013 Nov.

Abstract

Hypertension in the elderly substantially contributes to cerebromicrovascular damage and promotes the development of vascular cognitive impairment. Despite the importance of the myogenic mechanism in cerebromicrovascular protection, it is not well understood how aging affects the functional adaptation of cerebral arteries to high blood pressure. Hypertension was induced in young (3 months) and aged (24 months) C57/BL6 mice by chronic infusion of angiotensin II (AngII). In young hypertensive mice, the range of cerebral blood flow autoregulation was extended to higher pressure values, and the pressure-induced tone of middle cerebral artery (MCA) was increased. In aged hypertensive mice, autoregulation was markedly disrupted, and MCAs did not show adaptive increases in myogenic tone. In young mice, the mechanism of adaptation to hypertension involved upregulation of the 20-HETE (20-hydroxy-5,8,11,14-eicosatetraenoic acid)/transient receptor potential cation channel, subfamily C (TRPC6) pathway and this mechanism was impaired in aged hypertensive mice. Downstream consequences of cerebrovascular autoregulatory dysfunction in aged AngII-induced hypertensive mice included exacerbated disruption of the blood-brain barrier and neuroinflammation (microglia activation and upregulation of proinflammatory cytokines and chemokines), which were associated with impaired hippocampal dependent cognitive function. Collectively, aging impairs autoregulatory protection in the brain of mice with AngII-induced hypertension, potentially exacerbating cerebromicrovascular injury and neuroinflammation.

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Figures

Figure 1
Figure 1
Aging impairs adaptation of cerebrovascular autoregulation to hypertension. (A) Effect of chronic infusion of angiotensin II (AngII) on systolic blood pressure in young and aged mice. Data are mean±s.e.m. (n=20 to 25 for each group) *P<0.05 vs. Young; &P<0.05 vs. Aged. (B) Relationship between cerebral blood flow (CBF) and systolic blood pressure in young control, young hypertensive (Young+AngII), aged control, and aged hypertensive (Aged+AngII) mice. Data are mean±s.e.m. (n=8 in each group). In young control mice, CBF is statistically different from the value of 100 mm Hg at pressure values of <60 and >140 mm Hg, indicating the autoregulatory range. In young hypertensive mice, there was a progressive expansion of the autoregulated range, indicating an adaptive response (*P<0.05 vs. Young), which was completely absent in aged hypertensive mice (#P<0.05 vs. Young+AngII). (C) Steady-state changes in diameter of middle cerebral arteries (MCAs) isolated from each experimental group of mice in response to increases in intraluminal pressure, representing the static component of the myogenic response. Vascular diameters are expressed as a percentage of the maximally dilated passive diameter of each vessel at 80 mm Hg. (D) Changes in the diameter of MCAs to a sudden increase in intraluminal pressure (from 60 to 140 mm Hg), representing the dynamic component of the myogenic response. (E) Flow-induced constriction of MCAs (induced by increasing intraluminal flow by creating a pressure gradient through the vessels). Data are mean±s.e.m. (n=8 to 16). *P<0.05 vs. Young; #P<0.05 vs. Young+AngII; &P<0.05 vs. Aged.
Figure 2
Figure 2
Role of 20-hydroxy-5,8,11,14-eicosatetraenoic acid (20-HETE) mediation in cerebrovascular autoregulatory dysfunction in aged hypertensive mice. (A, B) The effect of HET0016 (10−6 mol/L), an inhibitor of 20-HETE synthesis, on myogenic constriction of middle cerebral arteries (MCAs) isolated from young control, young hypertensive (Young+AngII), aged control, and aged hypertensive (Aged+AngII) mice in response to increases in intraluminal pressure. Vascular diameters are expressed as a percentage of the passive diameter of the vessels at 80 mm Hg. (C) Myogenic tone of MCAs in the absence and presence of HET0016 at an intraluminal pressure of 160 mm Hg. Data are mean±s.e.m. (n=8 in each group). *P<0.05 vs. young and #P<0.05 vs. Young+AngII. (D, E) Effect of HET0016 on the early rapid phase of the myogenic response (D; induced by a sudden increase in intraluminal pressure from 60 to 140 mm Hg) and flow-induced constriction (E; induced by increasing intraluminal flow by creating a pressure gradient through the vessels; see Materials and methods) of MCAs. Data are mean±s.e.m. (n=8 to 16). #P<0.05 vs. Young+AngII. (F to H) QRT-PCR data showing mRNA expression of cytochrome P450 4A enzymes in MCAs. Data are mean±s.e.m. (n=6 in each group). *P<0.05 vs. Young; #P<0.05 vs. Young+AngII and &P<0.05 vs. Aged. AngII, angiotensin II.
Figure 3
Figure 3
Role of transient receptor potential cation channel, subfamily C (TRPC6) in cerebrovascular autoregulatory dysfunction in aged hypertensive mice. (A, B) The effect of SKF96365 (5 μmol/L), a TRPC channel blocker, and HET0016 (10−6 mol/L), an inhibitor of 20-hydroxy-5,8,11,14-eicosatetraenoic acid (20-HETE) synthesis, on myogenic constriction of middle cerebral arteries (MCAs) isolated from young control, young hypertensive (Young+AngII), aged control, and aged hypertensive (Aged+AngII) mice. Vascular diameters are expressed as a percentage of the passive diameter of the vessels at 80 mm Hg. (C) Myogenic tone of MCAs in the absence and presence of SKF96365 and HET0016 at an intraluminal pressure of 160 mm Hg. Data are mean±s.e.m. (n=8 in each group). *P<0.05 vs. Young and #P<0.05 vs. Young+AngII. (D, E) mRNA (D; QRT-PCR data) and protein expression (E; western blotting, one representative western blot (of three) is presented showing two samples from each group (for each group, n=6 vessels from 6 animals) of TRPC6 in MCAs. Data are mean±s.e.m. (n=6 in each group). *P<0.05 vs. Young and #P<0.05 vs. Young+AngII.
Figure 4
Figure 4
Aging exacerbates hypertension-induced disruption of the blood–brain barrier. (A) Hypertension- and aging-induced changes in sodium fluorescein content in the hippocampus, cortex, and white matter of young control, young hypertensive (Young+AngII), aged control, and aged hypertensive (Aged+AngII) mice. Data are mean±s.e.m. *P<0.05 vs. Young, #P<0.05 vs. Young+AngII; and &P<0.05 vs. Aged (n=6 to 10). (B) Confocal microscopy analysis of plasma-derived IgG (green) and CD31-positive microvessels (red) in the hippocampus of young and aged mice with or without AngII-induced hypertension. Note the increased presence of extravascular IgG deposits in the hippocampus of aged hypertensive mice. (C) Expression of occludin, claudin-5, and ZO-1 in the hippocampi of young and aged normotensive and hypertensive mice. Upper panels: original western blots. β-Actin was used as a loading control. One representative western blot (of three) is presented showing two samples from each group (for each group, n=6 vessels from 6 animals). Bar graphs are summary densitometric values. Data are mean±s.e.m. *P<0.05 vs. Young. n=6 animals per group. AngII, angiotensin II.
Figure 5
Figure 5
Hypertension-induced changes in pericyte coverage of hippocampal capillaries and hippocampal capillary density. (A) Representative confocal image showing perivascular localization of an α-smooth muscle actin (αSMA) expressing pericyte (green, arrowhead) surrounding CD31-positive capillary endothelial cells (red) in the CA1 region of the mouse hippocampus. Hoechst 33342 was used for nuclear counterstaining. (B to E) Representative confocal microscopy analysis of αSMA expressing pericyte coverage (green, arrowheads) of CD31-positive capillaries (red) in the CA1 region of the hippocampi of young control (B), young hypertensive (Young+AngII) (C), aged control (D), and aged hypertensive (Aged+AngII) (E) animals. Note that αSMA expressing pericytes (arrowheads) and vascular smooth muscle cells surrounding the terminal arterioles exhibit different morphologies. (F) Summary data showing hypertension-dependent loss of pericyte coverage in the hippocampus (see Supplementary Experimental Procedures for details). *P<0.05 vs. Young; #P<0.05 vs. Young+AngII; and &P<0.05 vs. Aged. (G) Hypertension-induced relative changes of capillary density in the CA1 and CA3 regions of the hippocampus, dentate gyrus (DG), retrosplenial cortex (RSA), primary somatosensory cortex (S1), and corpus callosum (cc) of young and aged mice. Boxes indicate brain regions that were included in the evaluation of capillary density (see Supplementary Experimental Procedures for details). AngII, angiotensin II.
Figure 6
Figure 6
Aging exacerbates hypertension-induced neuroinflammation and cognitive decline. (A to D) CD68-positive (red fluorescence, arrowheads) activated microglia in the hippocampus CA1 region from young control (A), young hypertensive (Young+AngII) (B), aged control (C1 and aged hypertensive (Aged+AngII) (D) animals (blue fluorescence: nuclei). Panel (E) shows that in the hippocampus of aged hypertensive mice most CD68-positive cells are positive for IBA1 (arrows), yet there are CD68+/IBA1− cells present as well (star). Panel (F) depicts summary data of relative changes in the number of CD68-positive activated microglia in the CA1 and CA3 regions of hippocampus (fold change). Data are mean±s.e.m. *P<0.05 vs. Young; #P<0.05 vs. Young+AngII; and &P<0.05 vs. Aged. (G) Hypertension in aging is associated with a proinflammatory shift in cytokine expression profiles in the mouse hippocampus. The heat map is a graphic representation of normalized mRNA expression of cytokines and chemokines depicted by color intensity, from highest (bright red) to lowest (bright blue) expression (n=6 in each group). Aged hypertensive mice have the highest expression of inflammatory markers. (H to K) Relative hippocampal levels of microglia-derived proinflammatory cytokines MCP-1 (H), TNFα (I) and IP-10 (J) and 3-nitrotyrosine (3-NT) (a marker for peroxynitrite action; K). Data are mean±s.e.m. *P<0.05 vs. Young; #P<0.05 vs. Young+AngII; and &P<0.05 vs. Aged. (L, M) Aging exacerbates hypertension-induced cognitive impairment (elevated plus maze-based learning protocol; see Supplementary Experimental Procedures for details). For old hypertensive mice, transfer latency was similar on days 1 and 2 (corresponding to a learning index: ∼0), indicating that these mice had significantly impaired hippocampal cognitive function. Data are mean±s.e.m. *P<0.05 vs. Young; #P<0.05 vs. Young+AngII; and &P<0.05 vs. Aged. (N) Proposed scheme depicting the mechanisms by which age-related cerebrovascular autoregulatory dysfunction exacerbates hypertension-induced microvascular damage and blood–brain barrier (BBB) disruption. Future studies should elucidate the links (dashed lines; question marks) among endothelial dysfunction, microvascular injury, regional ischemia, neuroinflammation, and cognitive impairment. AngII, angiotensin II; 20-HETE, 20-hydroxy-5,8,11,14-eicosatetraenoic acid.
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References

    1. Aronow WS, Fleg JL, Pepine CJ, Artinian NT, Bakris G, Brown AS, et al. ACCF/AHA 2011 expert consensus document on hypertension in the elderly: a report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents. Circulation. 2011;123:2434–2506. - PubMed
    1. Iadecola C, Park L, Capone C. Threats to the mind: aging, amyloid, and hypertension. Stroke. 2009;40:S40–S44. - PMC - PubMed
    1. Gorelick PB, Scuteri A, Black SE, Decarli C, Greenberg SM, Iadecola C, et al. Vascular contributions to cognitive impairment and dementia: a statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2011;42:2672–2713. - PMC - PubMed
    1. Brickman AM, Reitz C, Luchsinger JA, Manly JJ, Schupf N, Muraskin J, et al. Long-term blood pressure fluctuation and cerebrovascular disease in an elderly cohort. Arch Neurol. 2010;67:564–569. - PMC - PubMed
    1. Reitz C, Tang MX, Manly J, Mayeux R, Luchsinger JA. Hypertension and the risk of mild cognitive impairment. Arch Neurol. 2007;64:1734–1740. - PMC - PubMed

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