Loss of distensibility in cerebral arteries with chronic hypertension and vasospasm after subarachnoid hemorrhage

After subarachnoid hemorrhage (SAH), pathologic changes in cerebral arteries contribute to delayed cerebral ischemia and poor outcome. We hypothesize such changes are triggered by early intracellular signals, targeting of which may prevent SAH-induced vasculopathy. We performed an unbiased quantitative analysis of early SAH-induced phosphorylations in cerebral arteries and evaluated identified signaling components as targets for prevention of delayed vasculopathy and ischemia. Labeled phosphopeptides from rat cerebral arteries were quantified by high-resolution tandem mass spectrometry. Selected SAH-induced phosphorylations were validated by immunoblotting and monitored over a 24-hour time course post SAH. Moreover, inhibition of key phosphoproteins was performed. Major SAH-induced phosphorylations were observed on focal adhesion complexes, extracellular regulated kinase 1/2 (ERK1/2), calcium calmodulin-dependent kinase II, signal transducer and activator of transcription (STAT3) and c-Jun, the latter two downstream of ERK1/2. Inhibition of ERK1/2 6-hour post SAH prevented increases in cerebrovascular constrictor receptors, matrix metalloprotease-9, wall thickness, and improved neurologic outcome. STAT3 inhibition partially mimicked these effects. The study shows that quantitative mass spectrometry is a strong approach to study in vivo vascular signaling. Moreover, it shows that targeting of ERK1/2 prevents delayed pathologic changes in cerebral arteries and improves outcome, and identifies SAH-induced signaling components downstream and upstream of ERK1/2.

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Time Course of Changes in Nitric Oxide Synthases Following Subarachnoid Hemorrhage in Primates

Stroke ◽

10.1161/str.32.suppl_1.359-e ◽

2001 ◽

Vol 32 (suppl_1) ◽

pp. 359-360

Author(s):

Robert L Macdonald ◽

Bak Yamini ◽

Bryce K Weir ◽

Shigeki Ono

Keyword(s):

Nitric Oxide ◽

Subarachnoid Hemorrhage ◽

Time Course ◽

Cerebral Arteries ◽

Inflammatory Cells ◽

Inos Mrna ◽

Messenger Ribonucleic Acid ◽

Fold Reduction ◽

Middle Cerebral Arteries ◽

The Right

P114 Nitric oxide (NO) may be important in vasospasm following subarachnoid hemorrhage (SAH). We evaluated the time course of changes in 3 isoforms of NO synthase (NOS) after SAH in monkeys. Right SAH was created and vasospasm was assessed on angiograms obtained at baseline and after 3, 7 and 14 days. Animals were euthanized at these times (n = 4 - 6 per time) and the right and left (control) middle cerebral arteries were removed. Levels of nNOS, eNOS and iNOS messenger ribonucleic acid (mRNA) and protein were measured by reverse transcriptase polymerase chain reaction and Western blotting. Angiography showed a 45 ± 13% (mean ± s.d., p < 0.05) decrease in middle cerebral artery diameter 3 days, a 41 ± 23% (p< 0.05) decrease 7 days and an insignificant 6 ± 14% decrease 14 days after SAH. The RNA for eNOS was significantly reduced (1.7 ± 0.5-fold) 7 days after SAH. There was a significant, 1.7 ± 0.2-fold reduction in eNOS protein on days 3 and 7 after SAH that returned to normal by day 14. There were no significant changes in nNOS mRNA or protein at any time after SAH. There were no significant changes in iNOS mRNA whereas iNOS protein increased on days 3 and 7 (7 ± 9 and 2.7 ± 2.8-fold, respectively, p > 0.05) and significantly decreased (2.7 ± 1.1-fold, p < 0.05) on day 14. Immunohistochemistry localized eNOS to endothelium, nNOS to brain and perivascular adventitia of the middle cerebral arteries and iNOS to inflammatory cells in the subarachnoid space. These results show a correlation between decreased eNOS and increased iNOS during vasospasm, suggesting a complex role for changes in NO in vasospasm.

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Decreased Ca2+ Spark Frequency and RyR2 Expression in Cerebral Arteries Following Subarachnoid Hemorrhage

Biophysical Journal ◽

10.1016/j.bpj.2008.12.1379 ◽

2009 ◽

Vol 96 (3) ◽

pp. 278a-279a ◽

Cited By ~ 1

Author(s):

Masayo Koide ◽

Gayathri Krishnamoorthy ◽

Kevin P. O'Connor ◽

Matthew A. Nystoriak ◽

Mark T. Nelson ◽

...

Keyword(s):

Subarachnoid Hemorrhage ◽

Cerebral Arteries

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Evaluation of Vasospasm after Subarachnoid Hemorrhage by Use of Multislice Computed Tomographic Angiography

Neurosurgery ◽

10.1097/00006123-200210000-00015 ◽

2002 ◽

Vol 51 (4) ◽

pp. 939-943 ◽

Cited By ~ 7

Author(s):

Yasunari Otawara ◽

Kuniaki Ogasawara ◽

Akira Ogawa ◽

Makoto Sasaki ◽

Kei Takahashi

Keyword(s):

Subarachnoid Hemorrhage ◽

Cerebral Vasospasm ◽

Aneurysmal Subarachnoid Hemorrhage ◽

Cerebral Arteries ◽

Computed Tomographic Angiography ◽

Computed Tomographic ◽

Tomography System ◽

Middle Cerebral Arteries ◽

Multislice Images ◽

Tomographic Angiography

Abstract OBJECTIVE Multislice computed tomographic angiography (CTA) can provide clearer vascular images, even of the peripheral arteries, than conventional CTA. Multislice CTA was compared with digital subtraction angiography (DSA) for the detection of cerebral vasospasm in patients with acute aneurysmal subarachnoid hemorrhage (SAH) to analyze whether multislice CTA can replace DSA in the detection of vasospasm after SAH. METHODS Within 72 hours after the onset of symptoms, multislice CTA and DSA were performed in 20 patients with SAH. Multislice CTA and DSA were repeated on Day 7 to assess cerebral vasospasm. Regions of interest were established in the proximal and distal segments of the anterior and middle cerebral arteries on both multislice CTA and DSA images, and the agreement between the severity of vasospasm on multislice CTA and DSA images was statistically compared. The multislice Aquilon computed tomography system (Toshiba, Inc., Tokyo, Japan) used the following parameters: 1 mm collimation and 3.5 mm per rotation table increment (pitch, 3.5). RESULTS The degree of vasospasm as revealed by multislice CTA correlated significantly with the degree of vasospasm revealed by DSA (P < 0.0001). The agreement between the severity of vasospasm on multislice images obtained via CTA and DSA in the overall, proximal, and distal segments of the cerebral arteries was 91.6, 90.8, and 92.3%, respectively. CONCLUSION Multislice CTA can detect angiographic vasospasm after SAH with accuracy equal to that of DSA.

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Abstract 170: Arginase Contributes to Delayed Constriction of Large Cerebral Arteries in a Model of Subarachnoid Hemorrhage

Stroke ◽

10.1161/str.47.suppl_1.170 ◽

2016 ◽

Vol 47 (suppl_1) ◽

Author(s):

Weiyun Sun ◽

Kathleen K Kibler ◽

Herman Kwansa ◽

Ewa Kulikowicz ◽

Weizhu Tang ◽

...

Keyword(s):

Subarachnoid Hemorrhage ◽

Ex Vivo ◽

Cerebral Arteries ◽

Arginase Activity ◽

Male Rats ◽

Control Value ◽

Age Related ◽

Arterial Constriction ◽

Oxide Synthase ◽

Nitric Oxide Synthase Activity

Introduction: Increased arginase activity can limit nitric oxide synthase activity and contribute to age-related increase in aortic stiffness. Hypothesis: Subarachnoid hemorrhage (SAH) produces a delayed increase in arginase activity that contributes to delayed decreases in diameter of major cerebral arteries. Methods: Male rats underwent injection of blood into the cisterna magna on day 0 and again on day 2. Shams had double injection of artificial CSF. Measurements of arginase activity on vessels in the Circle of Willis and pia matter were made with an assay based on the conversion of radiolabeled arginine to urea. Measurements of diameter of basilar, posterior (PCA), middle (MCA), and anterior (ACA) cerebral arteries were made ex vivo after perfusion with paraformaldehyde and black latex casting. Results: Arginase activity (nmol of urea/min/mg of protein) increased from the control value of 13±3 (±SE; n=17) to 24±6 (n=6) at 3 days, 36±14 (n=4) at 5 days, and 48±16 (n=9) at 7 days after SAH and then recovered at 10 days (14±5; n=4) and 14 days (18±6; n=5) after SAH. Infusion of the arginase inhibitor 2(S)-amino-6-boronohexanoic acid (ABH) for 7 days after SAH with an ip osmotic pump blocked the increase in arginase activity (10±2; n=4). Assessment of arterial diameter at 3, 5, 7, 10, and 14 days after SAH revealed the smallest diameters occurring at 7 days (except for MCA which occurred at 5 days). Continuous ip infusion of 10 mg/kg/day ABH significantly attenuated the decrease in diameter (μm) 7 days after SAH in PCA (sham = 249±9, n=8; SAH = 209±12, n=10; SAH+ABH = 255±9, n=6) and ACA (sham = 178±11; SAH = 141±11; SAH+ABH = 198±10). Effects on basilar artery were of marginal significance (P=0.065). Conclusion: SAH produces an increase in vascular arginase activity that is temporally related to delayed decreases in diameter of cerebral arteries. Inhibition of arginase activity prevents the decrease in diameter at 7 days after SAH, thereby indicating a contribution of arginase to delayed arterial constriction/remodeling in post-fixed arteries.

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Changes in the Adrenergic Mechanisms of Cerebral Arteries after Subarachnoid Hemorrhage in Goats

Neurosurgery ◽

10.1097/00006123-199406000-00011 ◽

1994 ◽

Vol 34 (6) ◽

pp. 1027-1034

Author(s):

José A. Alabadí ◽

Germán Torregrosa ◽

Juan B. Salom ◽

Francisco J. Miranda ◽

Marìa D. Barberá ◽

...

Keyword(s):

Subarachnoid Hemorrhage ◽

Cerebral Arteries ◽

Adrenergic Mechanisms

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The influence of subarachnoid hemorrhage on alpha adrenergic receptors in human cerebral arteries

The Japanese Journal of Pharmacology ◽

10.1016/s0021-5198(19)59262-9 ◽

1986 ◽

Vol 40 ◽

pp. 172

Author(s):

Tetsuya Tsukahara ◽

Takashi Taniguchi ◽

Motohatsu Fujiwara

Keyword(s):

Subarachnoid Hemorrhage ◽

Adrenergic Receptors ◽

Cerebral Arteries ◽

Alpha Adrenergic Receptors

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Triphasic Response of Rat Intracerebral Arterioles to Increasing Concentrations of Vasopressin in vitro

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.1993.38 ◽

1993 ◽

Vol 13 (2) ◽

pp. 304-309 ◽

Cited By ~ 32

Author(s):

Masakazu Takayasu ◽

Yasukazu Kajita ◽

Yoshio Suzuki ◽

Masato Shibuya ◽

Kenichiro Sugita ◽

...

Keyword(s):

Subarachnoid Hemorrhage ◽

Vascular Tone ◽

Cerebral Arteries ◽

Specific Inhibitor ◽

In Vitro Study ◽

Relaxing Factor ◽

Pathological Conditions ◽

Cerebral Arterioles ◽

Endothelium Derived Relaxing Factor

To determine how vasopressin affects the vascular tone of the smaller cerebral arterioles, we carried out an in vitro study of isolated and cannulated intracerebral arterioles of rats. We found that increasing concentrations of vasopressin induced a triphasic response of vasodilation (10−12–10−11 M), vasoconstriction (10−10–10−8 M), and vasodilation stabilizing to control diameter (10−7–10−6 M) and that the maximum constriction was twice the maximum dilation in these smaller arterioles [21.2 ± 13.1% (mean ± SD) decrease in diameter vs. 11.2 ± 5.7% increase]. Pretreatment of the arterioles with NG-monomethyl-l-arginine (10−4 M), a specific inhibitor of endothelium-derived relaxing factor, abolished the vasopressin-induced vasodilation and significantly increased the vasoconstriction. These results suggest that these arterioles were maintained in a dilated state by an endothelium-derived relaxing factor activated by vasopressin. Both vasodilation and vasoconstriction were found to be mediated through vasopressin V1 receptors in a study of arterioles pretreated with d(CH2)5Tyr(Me)arginine vasopressin (10−6 M), a vasopressin V1 receptor antagonist. These results support the hypothesis that vasopressin may constrict smaller cerebral arterioles while simultaneously dilating larger cerebral arteries. Our results also suggest that vasopressin may aggravate cerebral ischemia in pathological conditions, such as subarachnoid hemorrhage, when the arteriolar response to vasopressin shifts from vasodilation to vasoconstriction due to increased vasopressin levels in plasma and CSF and impaired endothelium-derived relaxation.

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Ultrastructural evidence of arterial denervation following experimental subarachnoid hemorrhage

Journal of Neurosurgery ◽

10.3171/jns.1986.64.2.0292 ◽

1986 ◽

Vol 64 (2) ◽

pp. 292-297 ◽

Cited By ~ 33

Author(s):

Thomas A. Duff ◽

Grayson Scott ◽

John A. Feilbach

Keyword(s):

Subarachnoid Hemorrhage ◽

Prolonged Exposure ◽

Cerebral Arteries ◽

Content Type ◽

Ultrastructural Evidence ◽

Experimental Subarachnoid Hemorrhage ◽

Catecholamine Histofluorescence ◽

Increased Sensitivity ◽

The Media ◽

Adult Cats

✓ Loss of catecholamine histofluorescence, increased sensitivity to norepinephrine, and changes in alpha1 receptor binding have led to the proposal that denervation hypersensitivity may play a role in cerebrovascular spasm. Because the significance of these alterations has remained unclear, the present study was undertaken to determine whether there was direct ultrastructural evidence of arterial denervation following experimental subarachnoid hemorrhage. Under general anesthesia, adult cats were subjected to pre-pontine injection of blood or serum (5 to 7 ml) via a transclival approach. The animals were sacrificed 4, 7, or 10 days later and basilar artery segments were prepared for electron microscopy. Control vessels appeared normal, whereas those bathed in blood revealed unequivocal changes in neural and supporting elements, including: 1) disintegration of both clear- and dense-core vesicles; 2) fragmentation of varicosities; 3) loss of Schwann cell cytoplasm; and 4) axonal degeneration. These changes were most pronounced 7 days after instillation of blood, and correlated in time with maximal injury of the media and endothelium. Although the development of smooth-muscle hypersensitivity remains unsettled, this study indicates that prolonged exposure to blood can cause extensive denervation of cerebral arteries.

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