Endogenous Events Modulating Myogenic Regulation of Cerebrovascular Function

Cerebral parenchymal arterioles (PAs) have a critical role in assuring appropriate blood flow and perfusion pressure within the brain. They are unique in contrast to upstream pial arteries, as defined by their critical roles in neurovascular coupling, distinct sensitivities to chemical stimulants, and enhanced myogenic tone development. The objective of the present study was to reveal some of the unique mechanisms of myogenic tone regulation in the cerebral microcirculation. Here, we report that in vivo suppression of TRPM4 (transient receptor potential) channel expression, or inhibition of TRPM4 channels with 9-phenanthrol substantially reduced myogenic tone of isolated PAs, supporting a key role of TRPM4 channels in PA myogenic tone development. Further, downregulation of TRPM4 channels inhibited vasoconstriction induced by the specific P2Y4 and P2Y6 receptor ligands (UTP γS and UDP) by 37% and 42%, respectively. In addition, 9-phenanthrol substantially attenuated purinergic ligand-induced membrane depolarization and constriction of PAs, and inhibited ligand-evoked TRPM4 channel activation in isolated PA myocytes. In concert with our previous work showing the essential contributions of P2Y4 and P2Y6 receptors to myogenic regulation of PAs, the current results point to TRPM4 channels as an important link between mechanosensitive P2Y receptor activation and myogenic constriction of cerebral PAs.

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Abstract WP78: Intracranial Calcification is Predictive for Hemorrhage Transformation and Prognosis After Intravenous Thrombolysis

Stroke ◽

10.1161/str.51.suppl_1.wp78 ◽

2020 ◽

Vol 51 (Suppl_1) ◽

Author(s):

Yao Yu ◽

Fu-Liang Zhang ◽

Yin-Meng Qu ◽

Hong-Wei Zhou ◽

Zhenni Guo ◽

...

Keyword(s):

Ischemic Stroke ◽

Poor Prognosis ◽

Intravenous Thrombolysis ◽

Major Complication ◽

Third Party ◽

Intracranial Calcification ◽

Stroke Patients ◽

Anterior Circulation ◽

Cerebrovascular Function ◽

Lesion Side

Introduction: Hemorrhage transformation is the major complication of intravenous thrombolysis, which can deteriorate the prognosis of ischemic stroke patients. Calcification is widely used as an imaging indicator of atherosclerotic burden and cerebrovascular function. The relationship between intracranial calcification and hemorrhage transformation has not been fully explained. Here, we aimed to identify and quantify calcification in the main cerebral vessels to investigate the correlations between quantitative calcification parameters, hemorrhage transformation, and prognosis. Methods: Acute noncardiogenic ischemic stroke patients with anterior circulation who received intravenous thrombolysis therapy in the First Hospital of Jilin University from July 2015 to June 2017 were retrospectively consecutively included. All the patients included underwent a baseline CT before intravenous thrombolysis and a follow-up CT at 24 hours. A third-party software, ITK-SNAP, was used for segmentation and measurement of the calcification volume. A vascular non-bone component with a CT value >130 HU was judged to be calcified. The criterion for poor prognosis was an mRS score > 2 at 3 months. Results: A total of 146 patients were included, among which 128 patients were identified to have calcification. Twenty-one patients developed hemorrhage transformation. The risk of hemorrhage transformation in the extreme group of calcification volume on the lesion side was 10.018 times that of the none to mild groups (OR=10.018, 95% CI: 1.030-97.396). Sixty-one patients had poor prognosis. The risk of poor prognosis increased by 54.7% for each additional calcified vessel (OR=1.547, 95% CI: 1.038-2.305). Conclusions: High calcification volume burden on the lesion side is associated with hemorrhage transformation after intravenous thrombolysis. The higher the number of calcified vessels, the greater is the risk of poor prognosis.

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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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Resistance but not endurance exercise training induces changes in cerebrovascular function in healthy young subjects

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00230.2021 ◽

2021 ◽

Author(s):

Hannah J. Thomas ◽

Channa E. Marsh ◽

Louise H. Naylor ◽

Philip N. Ainslie ◽

Kurt J. Smith ◽

...

Keyword(s):

Resistance Training ◽

Arterial Pressure ◽

Endurance Training ◽

Acute Exercise ◽

Internal Carotid ◽

Cerebrovascular Reactivity ◽

Cerebral Hypoperfusion ◽

Brain Health ◽

Cerebrovascular Resistance ◽

Cerebrovascular Function

Aim: It is generally considered that regular exercise maintains brain health and reduces the risk of cerebrovascular diseases such as stroke and dementia. Since the benefits of different 'types' of exercise are unclear, we sought to compare the impacts of endurance and resistance training on cerebrovascular function. Methods: In a randomized and cross-over design, 68 young healthy adults were recruited to participate in 3-months of resistance and endurance training. Cerebral hemodynamics through the internal carotid, vertebral, middle and posterior cerebral arteries were measured using Duplex ultrasound and transcranial Doppler at rest and during acute exercise, dynamic autoregulation and cerebrovascular reactivity (to hypercapnia). Results: Following resistance, but not endurance training, middle cerebral artery velocity and pulsatility index significantly decreased (P<0.01 and P=0.02, respectively), while mean arterial pressure and cerebrovascular resistance in the middle, posterior and internal carotid arteries all increased (P<0.05). Cerebrovascular resistance in response to acute exercise and hypercapnia also significantly increased following resistance (P=0.02), but not endurance training. Conclusions: Our findings, which were consistent across multiple domains of cerebrovascular function, suggest that episodic increases in arterial pressure associated with resistance training may increase cerebrovascular resistance. The implications of long-term resistance training on brain health require future study, especially in populations with pre-existing cerebral hypoperfusion and/or hypotension.

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Residual chemosensitivity to ventilatory challenges in genotyped congenital central hypoventilation syndrome

Journal of Applied Physiology ◽

10.1152/japplphysiol.01310.2013 ◽

2014 ◽

Vol 116 (4) ◽

pp. 439-450 ◽

Cited By ~ 25

Author(s):

Michael S. Carroll ◽

Pallavi P. Patwari ◽

Anna S. Kenny ◽

Cindy D. Brogadir ◽

Tracey M. Stewart ◽

...

Keyword(s):

Young Adults ◽

Clinical Care ◽

Neurodevelopmental Disorder ◽

Control Group ◽

Congenital Central Hypoventilation Syndrome ◽

Specific Patient ◽

Cerebrovascular Function ◽

Central Hypoventilation ◽

Hypoventilation Syndrome ◽

Chemosensory Function

Congenital central hypoventilation syndrome (CCHS) is a neurodevelopmental disorder characterized by life-threatening hypoventilation, possibly resulting from disruption of central chemosensory integration. However, animal models suggest the possibility of residual chemosensory function in the human disease. Cardioventilatory function in a large cohort with CCHS and verified paired-like homeobox 2B ( PHOX2B) mutations was assessed to determine the extent and genotype dependence of any residual chemosensory function in these patients. As part of inpatient clinical care and evaluation, 64 distinct studies from 32 infants, children, and young adults with the disorder were evaluated for physiological response to three different inspired steady-state gas exposures of 3 min each: hyperoxia [100% oxygen (O2)]; hyperoxic hypercapnia [95% O2 and 5% carbon dioxide (CO2)]; and hypoxic hypercapnia [14% O2 and 7% CO2 balanced with nitrogen (N2)]. These were followed by a hypoxia challenge consisting of five or seven breaths of N2 (100% N2). In addition, a control group of 15 young adults was exposed to all but the hypoxic challenge. Comprehensive monitoring was used to derive breath-to-breath and beat-to-beat measures of ventilatory, cardiovascular, and cerebrovascular function. On average, patients showed a residual awake ventilatory response to chemosensory challenge, independent of the specific patient PHOX2B genotype. Graded dysfunction in cardiovascular regulation was found to associate with genotype, suggesting differential effects on different autonomic subsystems. In addition, differences between cases and controls in the cerebrovascular response to chemosensory challenge may indicate alterations in cerebral autoregulation. Thus residual cardiorespiratory responses suggest partial preservation of central nervous system networks that could provide a fulcrum for potential pharmacological interventions.

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Influence of exercise training on ischemic brain injury in type 1 diabetic rats

Journal of Applied Physiology ◽

10.1152/japplphysiol.00437.2012 ◽

2012 ◽

Vol 113 (7) ◽

pp. 1121-1127 ◽

Cited By ~ 16

Author(s):

Denise M. Arrick ◽

Hong Sun ◽

William G. Mayhan

Keyword(s):

Brain Injury ◽

Exercise Training ◽

Vascular Function ◽

Ischemia Reperfusion ◽

Diabetic Rats ◽

Ischemic Brain Injury ◽

Ischemic Brain ◽

Cerebrovascular Function ◽

Pial Arterioles

While exercise training (ExT) appears to influence cerebrovascular function during type 1 diabetes (T1D), it is not clear whether this beneficial effect extends to protecting the brain from ischemia-induced brain injury. Thus our goal was to examine whether modest ExT could influence transient focal ischemia-induced brain injury along with nitric oxide synthase (NOS)-dependent dilation of cerebral (pial) arterioles during T1D. Sprague-Dawley rats were divided into four groups: nondiabetic sedentary, nondiabetic ExT, diabetic (streptozotocin; 50 mg/kg ip) sedentary, and diabetic ExT. In the first series of studies, we measured infarct volume in all groups of rats following right MCA occlusion for 2 h, followed by 24 h of reperfusion. In a second series of studies, a craniotomy was performed over the parietal cortex, and we measured responses of pial arterioles to an endothelial NOS (eNOS)-dependent, a neuronal NOS (nNOS)-dependent, and a NOS-independent agonist in all groups of rats. We found that sedentary diabetic rats had significantly larger total, cortical, and subcortical infarct volumes following ischemia-reperfusion than sedentary nondiabetic, nondiabetic ExT, and diabetic ExT rats. Infarct volumes were similar in sedentary nondiabetic, ExT nondiabetic, and ExT diabetic rats. In contrast, ExT did not alter infarct size in nondiabetic compared with sedentary nondiabetic rats. In addition, ExT diabetic rats had impaired eNOS- and nNOS-dependent, but not NOS-independent, vasodilation that was restored by ExT. Thus ExT of T1D rats lessened ischemic brain injury following middle cerebral artery occlusion and restored impaired eNOS- and nNOS-dependent vascular function. Since the incidence of ischemic stroke is increased during T1D, we suggest that our finding are significant in that modest ExT may be a viable preventative therapeutic approach to lessen ischemia-induced brain injury that may occur in T1D subjects.

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