Abstract P213: Vascular Dysfunction and Aberrant Vascular NOTCH3 Signalling in Hypertension and Cerebral Autosomal Dominant Subcortical Infarcts and Leukoencephalopathy (CADASIL)

Hypertension ◽  
2016 ◽  
Vol 68 (suppl_1) ◽  
Author(s):  
Adam Harvey ◽  
Fiona Moreton ◽  
Augusto C Montezano ◽  
Aurelie Nguyen Dinh Cat ◽  
Paul Rocchiccioli ◽  
...  
Keyword(s):  
Er Stress ◽  
Vascular Function ◽  
Small Vessel Disease ◽  
Vascular Dysfunction ◽  
Gene Array ◽  
Rho Kinase ◽  
Small Vessel ◽  
Vessel Disease ◽  
Stress Markers ◽  
Clinical Conditions

Hypertension (HT) and CADASIL are clinical conditions of small vessel disease. Vascular dementia is a major feature in CADASIL, and a serious consequence of HT. CADASIL is a monogenic condition due to mutations in NOTCH3 , which is expressed almost exclusively in VSMCs. We hypothesised that altered NOTCH3 signalling in CADASIL and HT are associated with small vessel disease. Small arteries from gluteal biopsies from CADASIL patients (n=14), HT patients (n=3) and healthy controls (n=10) were investigated. Vascular function was assessed by myography. Cultured VSMCs were used to assess signaling through NOTCH3, NO, ER stress (gene array) and Rho kinase (ELISA). CADASIL and HT patients exhibited endothelial dysfunction (Max response: CADASIL 41.7±3%, HT 54.1±2% vs Control 98.2±4%). Pre-incubation with N-acetyl-cysteine ameliorated vasorelaxation. Only CADASIL displayed impaired endothelium-independent relaxation (Max response: CADASIL 53±1.9% vs Control 93±8.9%) and contraction (Max response: CADASIL 78±1.3% vs control 102±5%) (p<0.05). AngII-induced contraction was elevated in HT (98%), yet reduced in CADASIL (28%) (vs control 64% max contraction: p<0.05), despite VSMCs from both conditions displaying increased AT 1 R mRNA expression (HT: 5.1; CADASIL: 3.8; fold vs control; p<0.05). VSMCs from CADASIL and HT have decreased expression of CAMK1, SIRT2 and VEGFA; important in NO signalling (0.5 fold; p<0.05 vs control). VSMC levels of NOTCH3 and NOTCH ligand, JAG1, were increased in CADASIL (3.5, 2.5 fold) and HT (3.0, 2.6 fold, p<0.05). Downstream targets, HEY1 and HEYL, were elevated in CADASIL (3.8, 4.2 fold) and HT (1.9, 2.6 fold) (p<0.05). CADASIL but not HT VSMCs exhibited increased expression of ER stress markers. Rho kinase activity was increased in VSMCs from CADASIL (2.5 fold) and HT (2 fold) vs control (p<0.05). These data demonstrate that in CADASIL and HT, vascular dysfunction, is associated with aberrant NOTCH3 and Rho kinase signalling. In CADASIL, but not HT, endothelium-independent relaxation and ER stress were increased. Our results demonstrate a putative role for NOTCH3 -Rho kinase in vascular dysfunction in conditions of small vessel disease and suggest that ER stress and oxidative stress may be important in vascular injury in CADASIL.

Abstract MP42: Arterial Spin Labeling Imaging Assessment of Cerebrovascular Reactivity in Hypertensive Small Vessel Disease

Stroke ◽  
2021 ◽  
Vol 52 (Suppl_1) ◽  
Author(s):  
Hsin-Hsi C Tsai ◽  
Bo-Ching Lee ◽  
Abel Po-Hao Huang ◽  
Li-Kai Tsai ◽  
Ya-Fang Chen ◽  
...  
Keyword(s):  
Basal Ganglia ◽  
Arterial Spin Labeling ◽  
Small Vessel Disease ◽  
Vascular Dysfunction ◽  
Spin Labeling ◽  
Cerebrovascular Reactivity ◽  
Small Vessel ◽  
Disease Score ◽  
Temporal Lobes ◽  
Vessel Disease

Objective: Cerebrovascular reactivity (CVR) represents the phenomenon that cerebral vessels dilate or constrict in response to vasoactive stimuli, and CVR impairment may contribute to the brain injury caused by cerebral small vessel disease (SVD). We aim to determine the CVR in hypertensive intracerebral hemorrhage (ICH) and to identify its vascular dysfunction. Methods: 21 patients with spontaneous hypertensive ICH (strictly deep or mixed deep and lobar hemorrhages, mean age 62.5 ± 11.3 years) and 10 control subjects (mean age 66.1 ± 6.0) were enrolled for CVR measurement. Each participant received a brain MRI study, and CVR was calculated as cerebral blood flow (CBF) change using arterial spin labeling (ASL) sequence at baseline and 10 minutes after intravenous dipyridamole injection (0.57mg/Kg). Traditional MRI markers for SVD including cerebral microbleed, white matter hyperintensity, lacune and MRI-visible enlarged perivascular space were also evaluated to determine the total small vessel disease score. Results: Hypertensive ICH patients showed reduced CVR in the basal ganglia (CBF change 22.4 ± 22.7% vs. 41.7 ± 18.3, p=0.026), the frontal (15.1 ± 11.9 vs. 26.6 ± 9.9, p=0.013) and the temporal lobes (14.7 ± 11.1 vs. 26.2 ± 10.0, p=0.010) compared to control subjects (Figure). These differences remained significant in multivariable models after adjusting for age, sex, hypertension, diabetes, and hyperlipidemia. Within ICH groups, the CBF change in basal ganglia was significantly correlated with total small vessel disease score (R=-0.58, p=0.006), but not with individual MRI markers. Conclusion: Patients with advanced HTN-SVD demonstrated impaired vasoconstriction after dipyridamole challenge in basal ganglia, frontal and temporal lobes. Our findings provide safe approaches for whole brain CVR mapping in small vessel disease, and identify the potential physiological basis of vascular dysfunction in HTN-SVD.

scholarly journals Arterial Spin Labeling Imaging Assessment of Cerebrovascular Reactivity in Hypertensive Small Vessel Disease

2021 ◽  
Vol 12 ◽  
Author(s):  
Bo-Ching Lee ◽  
Hsin-Hsi Tsai ◽  
Abel Po-Hao Huang ◽  
Yen-Ling Lo ◽  
Li-Kai Tsai ◽  
...  
Keyword(s):  
Basal Ganglia ◽  
Arterial Spin Labeling ◽  
Small Vessel Disease ◽  
Vascular Dysfunction ◽  
Spin Labeling ◽  
Cerebrovascular Reactivity ◽  
Small Vessel ◽  
Disease Score ◽  
Vessel Disease ◽  
Control Subjects

Objective: Cerebrovascular reactivity (CVR) represents the phenomenon where cerebral vessels dilate or constrict in response to vasoactive stimuli. CVR impairment may contribute to brain injury due to cerebral small vessel disease (SVD). We aimed to determine the CVR in hypertensive intracerebral hemorrhage (ICH) and to identify its vascular dysfunction.Methods: A total of 21 patients with spontaneous hypertensive ICH (strictly deep or mixed deep and lobar hemorrhages, mean age 62.5 ± 11.3 years) and 10 control subjects (mean age 66.1 ± 6.0 years) were enrolled for CVR measurement at least 3 months after the symptomatic ICH event. Each participant underwent a brain MRI study, and CVR was calculated as the cerebral blood flow (CBF) reduction using arterial spin labeling (ASL) between baseline and 10 min after an intravenous dipyridamole injection (0.57 mg/kg). Traditional MRI markers for SVD were also evaluated, including cerebral microbleed, white matter hyperintensity, lacune, and MRI-visible enlarged perivascular space, which were used to determine the total small vessel disease score.Results: Compared to control subjects, hypertensive ICH patients showed reduced CVR in the basal ganglia (CBF reduction 22.4 ± 22.7% vs. 41.7 ± 18.3, p = 0.026), the frontal lobe (15.1 ± 11.9 vs. 26.6 ± 9.9, p = 0.013), and the temporal lobe (14.7 ± 11.1 vs. 26.2 ± 10.0, p = 0.010). These differences remained significant in multivariable models after adjusting for age and sex. Within ICH groups, the CBF reduction in the basal ganglia was significantly correlated with the total small vessel disease score (R = 0.58, p = 0.006), but not with individual MRI markers.Conclusion: Patients with advanced hypertensive SVD demonstrated impaired vasoconstriction after dipyridamole challenge in the basal ganglia and the frontal and temporal lobes. Our findings provide safe approaches for whole-brain CVR mapping in SVD and identify a potential physiological basis for vascular dysfunction in hypertensive SVD.

Abstract MP31: Peripheral Vascular Dysfunction In A Model Of Small Vessel Disease Of The Brain (CADASIL) Involves Impaired Redox-sensitive Cyclic GMP/PKG Signaling

Hypertension ◽  
2020 ◽  
Vol 76 (Suppl_1) ◽  
Author(s):  
Karla B Neves ◽  
Hannah Morris ◽  
Rheure Alves-lopes ◽  
Augusto C Montezano ◽  
Rhian M Touyz
Keyword(s):  
Soluble Guanylate Cyclase ◽  
Small Vessel Disease ◽  
Vascular Dysfunction ◽  
Plasma Lipid ◽  
Fold Increase ◽  
Mesenteric Arteries ◽  
Small Vessel ◽  
Resistance Arteries ◽  
Vessel Disease ◽  
The Brain

CADASIL, a monogenic condition due to Notch3 mutations, is a very aggressive small vessel disease of the brain resulting in premature vascular dementia and stroke. Changes in cerebral vessels include vascular dysfunction and narrowing, and accumulation of granular osmiophilic material (GOM). It is not clear whether small peripheral arteries undergo similar damage. Therefore, our aim is to assess vascular dysfunction and associated mechanisms in mesenteric resistance arteries from CADASIL mice. Mesenteric arteries (MA) from male CADASIL-causing Notch3 mutation (TgNotch3 R169C ) and wildtype (TgNotch3 WT ) mice (6 months old) were investigated. GOM deposits in MA from CADASIL mice were identified by electron microscopy. mRNA expression of Notch3 (WT: 2.0±0.5 vs. 6.0±1.3) and its downstream target HeyL (WT: 1.1±0.4 vs. 2.9±0.6) was augmented in CADASIL mice (p<0.01), suggesting increased Notch3 activation. CADASIL mice exhibited endothelial-dependent (Emax 109.9±7.4 vs. 81.3±5.4) and -independent dysfunction (pD 2 7.8±0.1 vs. 6.8±0.3); effects associated with increased eNOS inhibition (p-Thr 495 ) (1.8-fold increase) and decreased cGMP levels (1.2±0.2 vs. 0.59±0.2) (p<0.05). Plasma lipid peroxidation (0.8±0.1 vs. 2.0±0.3; p<0.05) and vascular reactive oxygen species (ROS) production (7.2±1.9 vs. 75.4±35.0; p<0.05) were increased in TgNotch3 R169C mice; processes associated with upregulation of soluble guanylate cyclase (sGC) oxidation and decreased sGC activity. H 2 O 2 levels were decreased in TgNotch3 R169C mice (1.9±0.2 vs. 1.1±1.9; p<0.05), which was associated with reduced activation of protein kinase G (PKG). Observations in TgNotch3 R169C mice were recapitulated in human CADASIL, where ROS levels (0.8±0.1 vs. 4.1±2.7; p<0.05) and sGC oxidation were also increased. Our findings demonstrate that the vasculopathy associated with a CADASIL Notch3 gain-of-function mutation in peripheral small vessels involves reduction in eNOS activation and redox-sensitive processes leading to impaired sGC/cGMP signalling pathway. We identify a potential new therapeutic target in CADASIL, for which there are no disease-specific treatments.

scholarly journals Heavy Metal-Induced Cerebral Small Vessel Disease: Insights into Molecular Mechanisms and Possible Reversal Strategies

2020 ◽  
Vol 21 (11) ◽  
pp. 3862 ◽  
Author(s):  
Jayant Patwa ◽  
Swaran Jeet Singh Flora
Keyword(s):  
Heavy Metals ◽  
Heavy Metal ◽  
Blood Vessels ◽  
Small Vessel Disease ◽  
Vascular Dysfunction ◽  
Cerebral Small Vessel Disease ◽  
Small Vessel ◽  
Amyloid Angiopathy ◽  
Vessel Disease ◽  
Antioxidant Defense Enzymes

Heavy metals are considered a continuous threat to humanity, as they cannot be eradicated. Prolonged exposure to heavy metals/metalloids in humans has been associated with several health risks, including neurodegeneration, vascular dysfunction, metabolic disorders, cancer, etc. Small blood vessels are highly vulnerable to heavy metals as they are directly exposed to the blood circulatory system, which has comparatively higher concentration of heavy metals than other organs. Cerebral small vessel disease (CSVD) is an umbrella term used to describe various pathological processes that affect the cerebral small blood vessels and is accepted as a primary contributor in associated disorders, such as dementia, cognitive disabilities, mood disorder, and ischemic, as well as a hemorrhagic stroke. In this review, we discuss the possible implication of heavy metals/metalloid exposure in CSVD and its associated disorders based on in-vitro, preclinical, and clinical evidences. We briefly discuss the CSVD, prevalence, epidemiology, and risk factors for development such as genetic, traditional, and environmental factors. Toxic effects of specific heavy metal/metalloid intoxication (As, Cd, Pb, Hg, and Cu) in the small vessel associated endothelium and vascular dysfunction too have been reviewed. An attempt has been made to highlight the possible molecular mechanism involved in the pathophysiology, such as oxidative stress, inflammatory pathway, matrix metalloproteinases (MMPs) expression, and amyloid angiopathy in the CSVD and related disorders. Finally, we discussed the role of cellular antioxidant defense enzymes to neutralize the toxic effect, and also highlighted the potential reversal strategies to combat heavy metal-induced vascular changes. In conclusion, heavy metals in small vessels are strongly associated with the development as well as the progression of CSVD. Chelation therapy may be an effective strategy to reduce the toxic metal load and the associated complications.

scholarly journals Small Vessel Disease-Related Dementia: An Invalid Neurovascular Coupling?

2020 ◽  
Vol 21 (3) ◽  
pp. 1095 ◽  
Author(s):  
Rita Moretti ◽  
Paola Caruso
Keyword(s):  
Vascular Dementia ◽  
Vascular Function ◽  
Aging Process ◽  
Healthy Aging ◽  
Inflammatory Responses ◽  
Small Vessel Disease ◽  
Neurovascular Coupling ◽  
Small Vessel ◽  
Vessel Disease ◽  
Subcortical Vascular Dementia

The arteriosclerosis-dependent alteration of brain perfusion is one of the major determinants in small vessel disease, since small vessels have a pivotal role in the brain’s autoregulation. Nevertheless, as far as we know, endothelium distress can potentiate the flow dysregulation and lead to subcortical vascular dementia that is related to small vessel disease (SVD), also being defined as subcortical vascular dementia (sVAD), as well as microglia activation, chronic hypoxia and hypoperfusion, vessel-tone dysregulation, altered astrocytes, and pericytes functioning blood-brain barrier disruption. The molecular basis of this pathology remains controversial. The apparent consequence (or a first event, too) is the macroscopic alteration of the neurovascular coupling. Here, we examined the possible mechanisms that lead a healthy aging process towards subcortical dementia. We remarked that SVD and white matter abnormalities related to age could be accelerated and potentiated by different vascular risk factors. Vascular function changes can be heavily influenced by genetic and epigenetic factors, which are, to the best of our knowledge, mostly unknown. Metabolic demands, active neurovascular coupling, correct glymphatic process, and adequate oxidative and inflammatory responses could be bulwarks in defense of the correct aging process; their impairments lead to a potentially catastrophic and non-reversible condition.

Abstract P242: Microvascular Changes in Brain During Salt-sensitive Hypertension: Molecular Mechanisms and Implications for Small Vessel Disease

Hypertension ◽  
2016 ◽  
Vol 68 (suppl_1) ◽  
Author(s):  
Travice M De Silva ◽  
Justin Grobe ◽  
Frank Faraci
Keyword(s):  
Molecular Mechanisms ◽  
Small Vessel Disease ◽  
Rho Kinase ◽  
Renin Angiotensin System ◽  
Microvascular Dysfunction ◽  
Small Vessel ◽  
Vessel Disease ◽  
Microvascular Changes ◽  
Pial Arterioles ◽  
The Brain

Hypertension is a major risk factor for small vessel disease (SVD), a leading contributor to stroke and dementias. Mechanisms that underlie SVD in brain are poorly defined, with no specific therapy at present. Because parenchymal and pial arterioles are targets of the SVD process, we examined microvascular changes in a model using deoxycorticosterone-salt (DOCA) to activate the brain renin-angiotensin system (RAS), with resulting salt-sensitive (sodium- and fluid-dependent) hypertension. Male C57Bl/6 mice were treated with DOCA and given the choice of drinking H 2 O or H 2 O with 0.9% NaCl for 3 wks. Along with a modest elevation in mean arterial pressure (79±2 vs 95±3 mmHg, P<0.05), DOCA impaired endothelium-dependent dilation of both isolated parenchymal (baseline diameter of 15±1 μm) and pial arterioles (37±1 μm) in a pathway specific manner. Endothelium-dependent hyperpolarization was intact while eNOS-mediated vasodilation was markedly impaired along with reductions in phosphorylation in AKT (an upstream activator of eNOS). Local inhibition of angiotensin II type 1 (AT1-R) or mineralocorticoid receptors (MR) or Rho kinase (including ROCK2), restored endothelial function in DOCA-treated mice. Inner diameter of maximally dilated parenchymal arterioles was reduced approximately 20% by DOCA (P<0.05 vs sham). DOCA increased mRNA expression of RAS components (eg, AGT, ACE) in both brain and cerebral vessels. In NZ44 reporter mice that express GFP driven by the AT1A-R promoter, DOCA increased cerebrovascular GFP protein expression about 3-fold (P<0.05). Thus, DOCA activates both the brain and the cerebrovascular RAS, impairs select pathways affecting parenchymal and pial arteriolar function, while producing inward microvascular remodeling. AT1R, MR and ROCK2 are key contributors to cerebral microvascular dysfunction in this clinically relevant model of SVD.

Abstract 33: Endoplasmic Reticulum Stress and Vascular Dysfunction in Hypertension

2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
Modar Kassan ◽  
Maria Galan ◽  
Megan Partyka ◽  
Daniel Henrion ◽  
Mohamed Trebak ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Vascular Function ◽  
Vascular Dysfunction ◽  
Ang Ii ◽  
Resistance Arteries ◽  
Cardiac Damage ◽  
Stress Markers ◽  
Enos Phosphorylation ◽  
Dependent Mechanism

Objective: Cardiac damage and vascular dysfunction are major causes of morbidity and mortality in hypertension. In this study, we explored the beneficial therapeutic effect of endoplasmic reticulum (ER) stress inhibition on cardiac damage and vascular dysfunction in hypertension. Methods & results: Mice were infused with angiotensin II (Ang-II, 400 ng/kg/min) with or without ER stress inhibitors (Tudca and PBA) for two weeks. Mice infused with Ang-II displayed an increase in blood pressure, cardiac hypertrophy and fibrosis associated with enhanced collagen-I content, TGFβ1 activity, and ER stress markers, which were blunted after ER stress inhibition. Hypertension induced ER stress in aorta and mesenteric resistance arteries (MRA), enhanced TGFβ1 activity in aorta but not in MRA, and reduced eNOS phosphorylation and endothelium-dependent relaxation (EDR) in aorta and MRA. The inhibition of ER stress significantly reduced TGFβ1 activity, enhanced eNOS phosphorylation and improved EDR. The inhibition of TGFβ1 pathway improved EDR in aorta but not in MRA, while the reduction in ROS levels ameliorated EDR in MRA only. Infusion of tunicamycin in control mice induced ER stress in aorta and MRA, and reduced EDR by a TGFβ1-dependent mechanism in aorta and ROS-dependent mechanism in MRA. Conclusion: ER stress inhibition reduces cardiac damage and improves vascular function in hypertension. Therefore ER stress could be a potential target for cardiovascular diseases.

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