Modulation of p66Shc impairs cerebrovascular myogenic tone in low renin but not low nitric oxide models of systemic hypertension

Cerebral blood flow and perfusion are tightly maintained through autoregulation despite changes in transmural pressure. Oxidative stress impairs cerebral blood flow, precipitating cerebrovascular events. Phosphorylation of the adaptor protein p66Shc increases mitochondrial-derived oxidative stress. The effect of p66Shc gain or loss of function in non-hypertensive rats is unclear. We hypothesized that p66Shc gain of function would impair autoregulation of cerebral microcirculation under physiological and pathological conditions. Three previously established transgenic (salt-sensitive background; SS) p66Shc rats were utilized, p66-Del/SS (express p66Shc with a 9-amino acid deletion), p66Shc-KO/SS (frameshift premature termination codon), and p66Shc-S36A/SS (substitution of Ser36Ala). The p66Shc-Del were also bred on Sprague-Dawley backgrounds (p66-Del/SD), and a subset was exposed to a hypertensive stimulus (L-NAME) for 4 weeks. Active and passive diameters to increasing transmural pressure were measured and myogenic tone was calculated. Myogenic responses to increasing pressure were impaired in p66Shc-Del/SS rats relative to WT/SS and knock-in substitution of S36A (P<0.05). p66-Del/SD rats did not demonstrate changes in active/passive diameters or myogenic tone relative to WT/SD, but did demonstrate attenuated passive diameter responses to higher transmural pressure relative to p66-Del/SS. 4 weeks of a hypertensive stimulus (L-NAME) did not alter active or passive diameter responses to increasing transmural pressure (P=0.86-0.99), but increased myogenic responses relative to p66-Del/SD (P<0.05). Collectively, we demonstrate the functional impact of modulation of p66Shc within the cerebral circulation and demonstrate that the genetic background of p66Shc rats largely drives changes in cerebrovascular function.

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Abstract WP498: Impaired Pericyte Constriction and Cerebral Blood Flow Autoregulationin Diabetes

Stroke ◽

10.1161/str.51.suppl_1.wp498 ◽

2020 ◽

Vol 51 (Suppl_1) ◽

Author(s):

Yedan Liu ◽

Shaoxun Wang ◽

Ya Guo ◽

Huawei Zhang ◽

Richard Roman ◽

...

Keyword(s):

Blood Flow ◽

Cerebral Blood Flow ◽

Ex Vivo ◽

Mitochondrial Dynamics ◽

Vascular Cognitive Impairment ◽

Treated Group ◽

Diabetic Rats ◽

Cerebrovascular Function

Diabetes is the primary pathological factor attributed to Alzheimer’s disease and vascular cognitive impairment. Previous studies demonstrated that hyperglycemia promoted oxidative stress in the cerebral vasculature. Cerebrovascular pericytes contribute to maintaining blood-brain barrier (BBB) integrity and regulating cerebral blood flow (CBF). However, whether hyperglycemia diminishes the contractile capability of pericytes, impairs CBF autoregulation and increases BBB permeability are unclear. In the present study, we examined the role of pericytes in cerebrovascular function and cognition in diabetes using cell culture in vitro , isolated penetrating arterioles ex vivo and CBF autoregulation in vivo . Reactive oxygen species were elevated in high glucose (HG, 30 mM) treated vs. normal glucose (NG, 5.5 mM) treated pericytes. Further, mitochondrial superoxide production was increased in HG-treated vs. NG-treated group (13.24 ± 1.01 arbitrary unit (a.u.)/30min vs. 6.98 ± 0.36 a.u./30min). Mitochondrial respiration decreased in HG-treated vs. NG-treated pericytes (3718 ± 185.9 pmol/min/mg, n=10 vs. 4742 ± 284.5 pmol/min/mg, n=10) as measured by a Seahorse XFe24 analyzer. HG-treated pericytes displayed fragmented mitochondria in association with increased fission protein (DRP1) and decreased fusion protein (OPA1) expression. HG-treated pericytes displayed lower contractile capability than NG-treated cells (20.23 ± 7.15% vs. 29.46 ± 9.41%). The myogenic response was impaired in penetrating arterioles isolated from diabetic rats in comparison with non-diabetic rats. Autoregulation of CBF measured by a laser Doppler flowmeter was impaired in diabetic rats compared with non-diabetic rats. Diabetic rats exhibited greater BBB leakage than control rats. The cognitive function was examined using an eight-arm water maze. Diabetic rats took longer time to escape than the non-diabetic rats indicating learning and memory deficits. In conclusion, hyperglycemia induces pericyte dysfunction by altering mitochondrial dynamics and diminishing contractile capability, which promotes BBB leakage, decreases CBF autoregulation and contributes to diabetes-related dementia.

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The Contribution of Arterial Blood Gases in Cerebral Blood Flow Regulation and Fuel Utilization in Man at High Altitude

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.2015.4 ◽

2015 ◽

Vol 35 (5) ◽

pp. 873-881 ◽

Cited By ~ 25

Author(s):

Christopher K Willie ◽

David B MacLeod ◽

Kurt J Smith ◽

Nia C Lewis ◽

Glen E Foster ◽

...

Keyword(s):

Blood Flow ◽

Cerebral Blood Flow ◽

High Altitude ◽

Cerebral Metabolism ◽

Venous Blood ◽

Blood Gases ◽

Cerebrovascular Reactivity ◽

Arterial Blood Gases ◽

Arterial Blood ◽

Cerebrovascular Function

The effects of partial acclimatization to high altitude (HA; 5,050 m) on cerebral metabolism and cerebrovascular function have not been characterized. We hypothesized (1) increased cerebrovascular reactivity (CVR) at HA; and (2) that CO2 would affect cerebral metabolism more than hypoxia. PaO2 and PaCO2 were manipulated at sea level (SL) to simulate HA exposure, and at HA, SL blood gases were simulated; CVR was assessed at both altitudes. Arterial–jugular venous differences were measured to calculate cerebral metabolic rates and cerebral blood flow (CBF). We observed that (1) partial acclimatization yields a steeper CO2-H+ relation in both arterial and jugular venous blood; yet (2) CVR did not change, despite (3) mean arterial pressure (MAP)-CO2 reactivity being doubled at HA, thus indicating effective cerebral autoregulation. (4) At SL hypoxia increased CBF, and restoration of oxygen at HA reduced CBF, but neither had any effect on cerebral metabolism. Acclimatization resets the cerebrovasculature to chronic hypocapnia.

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Sympathetic regulation of cerebral blood flow during reflex hypertension

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1985.249.3.h672 ◽

1985 ◽

Vol 249 (3) ◽

pp. H672-H680

Author(s):

P. Lacombe ◽

M. C. Miller ◽

J. Seylaz

Keyword(s):

Blood Flow ◽

Cerebral Blood Flow ◽

Brain Structures ◽

Systemic Hypertension ◽

Regional Cerebral Blood ◽

Acute Hypertension ◽

Cerebrovascular Autoregulation ◽

Circulatory Effects ◽

Sympathetic Regulation ◽

The Brain

The cerebral circulatory effects of physiological stimulation of the sympathetic nervous system have been examined in the present study. In lightly anesthetized rabbits, reflex sympathetic activation was provoked by bilateral sinus deafferentation and vagotomy. Regional cerebral blood flow (CBF) was measured by the [14C]-ethanol technique and compared in paired brain structures following unilateral superior cervical ganglionectomy. Two subgroups of hypertensive rabbits were statistically distinguished. In the first (19 of 28 rabbits), CBF in the innervated hemisphere was little modified by hypertension but there was a significant side-to-side difference in CBF between the hemispheres. In the second group (9 rabbits) CBF was markedly increased by the systemic hypertension, and little difference was noted between innervated and denervated hemispheres. We demonstrate that, during acute hypertension, the superior cervical system contributes to cerebrovascular autoregulation; this contribution varies according to the brain region studied. In a subgroup of animals, little sympathetic activity could be evidenced, and it is hypothesized that in these rabbits a vasodilatory system was activated that counteracted the myogenic, autoregulatory responses.

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The Renin-Angiotensin System and the Cerebrovascular Diseases: Experimental and Clinical Evidence

Protein and Peptide Letters ◽

10.2174/0929866527666191218091823 ◽

2020 ◽

Vol 27 (6) ◽

pp. 463-475 ◽

Cited By ~ 5

Author(s):

Lucas M. Kangussu ◽

Lucas Alexandre Santos Marzano ◽

Cássio Ferraz Souza ◽

Carolina Couy Dantas ◽

Aline Silva Miranda ◽

...

Keyword(s):

Oxidative Stress ◽

Blood Flow ◽

Cerebral Blood Flow ◽

Renin Angiotensin System ◽

Cerebrovascular Diseases ◽

Therapeutic Effects ◽

Angiotensin System ◽

Renin Angiotensin ◽

Mas Receptor

Cerebrovascular Diseases (CVD) comprise a wide spectrum of disorders, all sharing an acquired or inherited alteration of the cerebral vasculature. CVD have been associated with important changes in systemic and tissue Renin-Angiotensin System (RAS). The aim of this review was to summarize and to discuss recent findings related to the modulation of RAS components in CVD. The role of RAS axes is more extensively studied in experimentally induced stroke. By means of AT1 receptors in the brain, Ang II hampers cerebral blood flow and causes tissue ischemia, inflammation, oxidative stress, cell damage and apoptosis. On the other hand, Ang-(1-7) by stimulating Mas receptor promotes angiogenesis in brain tissue, decreases oxidative stress, neuroinflammation, and improves cognition, cerebral blood flow, neuronal survival, learning and memory. In regard to clinical studies, treatment with Angiotensin Converting Enzyme (ACE) inhibitors and AT1 receptor antagonists exerts preventive and therapeutic effects on stroke. Besides stroke, studies support a similar role of RAS molecules also in traumatic brain injury and cerebral aneurysm. The literature supports a beneficial role for the alternative RAS axis in CVD. Further studies are necessary to investigate the therapeutic potential of ACE2 activators and/or Mas receptor agonists in patients with CVD.

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Hypoxia mediated pulmonary edema: potential influence of oxidative stress, sympathetic activation and cerebral blood flow

BMC Physiology ◽

10.1186/s12899-015-0018-4 ◽

2015 ◽

Vol 15 (1) ◽

Cited By ~ 6

Author(s):

Shadi Khademi ◽

Melinda A. Frye ◽

Kimberly M. Jeckel ◽

Thies Schroeder ◽

Eric Monnet ◽

...

Keyword(s):

Oxidative Stress ◽

Blood Flow ◽

Cerebral Blood Flow ◽

Pulmonary Edema ◽

Sympathetic Activation ◽

Potential Influence

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Neutrophil adhesion in brain capillaries contributes to cerebral blood flow deficits in APP/PS1 mice and is dependent on oxidative stress pathways

Alzheimer s & Dementia ◽

10.1002/alz.043267 ◽

2020 ◽

Vol 16 (S2) ◽

Author(s):

Nancy E. Ruiz‐Uribe ◽

Oliver Bracko ◽

Madison Swallow ◽

Muhammad Ali ◽

Brendah N. Njiru ◽

...

Keyword(s):

Oxidative Stress ◽

Blood Flow ◽

Cerebral Blood Flow ◽

Neutrophil Adhesion ◽

Brain Capillaries

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Endothelium-dependent contraction to stretch in canine basilar arteries

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1987.252.3.h671 ◽

1987 ◽

Vol 252 (3) ◽

pp. H671-H673 ◽

Cited By ~ 16

Author(s):

Z. S. Katusic ◽

J. T. Shepherd ◽

P. M. Vanhoutte

Keyword(s):

Blood Flow ◽

Smooth Muscle ◽

Cerebral Blood Flow ◽

Vascular Smooth Muscle ◽

Calcium Entry ◽

Transmural Pressure ◽

Active Tension ◽

Basilar Arteries

Stretch applied to isolated canine basilar arteries caused the development of active tension in rings with endothelium but not in those in which the endothelium had been removed. Blockade of calcium entry with diltiazem or inhibition of cyclooxygenase with indomethacin abolished the endothelium-dependent response to stretch. These observations suggest that the endothelium may contribute to the autoregulation of cerebral blood flow during increases in transmural pressure by the increased production and/or release of prostaglandins, which causes activation of the underlying vascular smooth muscle.

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The Effect of Infusions of Adrenaline, Noradrenaline and Dopamine on Cerebral Autoregulation under Isoflurane Anaesthesia in an Ovine Model

Anaesthesia and Intensive Care ◽

10.1177/0310057x0303100303 ◽

2003 ◽

Vol 31 (3) ◽

pp. 259-266 ◽

Cited By ~ 4

Author(s):

J. A. Myburgh ◽

R. N. Upton ◽

C. Grant ◽

A. Martinez

Keyword(s):

Blood Flow ◽

Cerebral Blood Flow ◽

Cerebral Autoregulation ◽

Dose Range ◽

Linear Regression Analysis ◽

Systemic Hypertension ◽

Dependent Manner ◽

Isoflurane Anaesthesia ◽

Awake State ◽

Significant Difference

The effects of infusions of adrenaline, noradrenaline and dopamine on cerebral autoregulation under steady-state isoflurane anaesthesia were compared with the awake state. Six studies each were conducted in two cohorts of adult ewes: awake sheep and those anaesthetized with 2% isoflurane anaesthesia. In random order, each animal received ramped infusions of adrenaline, noradrenaline (0-40 μg/min) and dopamine (0-40 μg/kg/min). Cerebral blood flow was measured continuously from changes in Doppler velocities in the sagittal sinus. Autoregulation was determined by linear regression analysis between cerebral blood flow and mean arterial pressure. Isoflurane did not significantly alter cerebral blood flow relative to pre-anaesthesia values (P>0.05). All three catecholamines significantly and equivalently increased MAP from baseline in a dose dependent manner in both the awake and isoflurane cohorts. Although adrenaline significantly increased cerebral blood flow from baseline in the awake cohort (P< 0.01), none of the catecholamines significantly increased cerebral blood flow during isoflurane anaesthesia. No significant differences were demonstrated between the slopes and intercepts of regression lines for adrenaline, noradrenaline and dopamine within either cohort (ANCOVA). Inter-cohort comparisons between the two autoregulation curves demonstrated no significant difference between the slopes of the autoregulation curves for the awake (pooled slope=0.39) and isoflurane cohorts (pooled slope=0.28) (P>0.05). Over a specific dose range, systemic hypertension induced by adrenaline, noradrenaline and dopamine did not significantly increase cerebral blood flow under 2% isoflurane anaesthesia. The concomitant administration of isoflurane and the catecholamines was not associated with altered autoregulatory function compared to the awake state.

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