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.

scholarly journals Role of Purinergic Signalling in Endothelial Dysfunction and Thrombo-Inflammation in Ischaemic Stroke and Cerebral Small Vessel Disease

Biomolecules ◽  
2021 ◽  
Vol 11 (7) ◽  
pp. 994
Author(s):  
Natasha Ting Lee ◽  
Lin Kooi Ong ◽  
Prajwal Gyawali ◽  
Che Mohd Nasril Che Mohd Nassir ◽  
Muzaimi Mustapha ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Endothelial Dysfunction ◽  
Inflammatory Response ◽  
Small Vessel Disease ◽  
Ischemia Reperfusion ◽  
Cerebral Small Vessel Disease ◽  
Small Vessel ◽  
Purinergic Signalling ◽  
Vessel Disease ◽  
The Brain

The cerebral endothelium is an active interface between blood and the central nervous system. In addition to being a physical barrier between the blood and the brain, the endothelium also actively regulates metabolic homeostasis, vascular tone and permeability, coagulation, and movement of immune cells. Being part of the blood–brain barrier, endothelial cells of the brain have specialized morphology, physiology, and phenotypes due to their unique microenvironment. Known cardiovascular risk factors facilitate cerebral endothelial dysfunction, leading to impaired vasodilation, an aggravated inflammatory response, as well as increased oxidative stress and vascular proliferation. This culminates in the thrombo-inflammatory response, an underlying cause of ischemic stroke and cerebral small vessel disease (CSVD). These events are further exacerbated when blood flow is returned to the brain after a period of ischemia, a phenomenon termed ischemia-reperfusion injury. Purinergic signaling is an endogenous molecular pathway in which the enzymes CD39 and CD73 catabolize extracellular adenosine triphosphate (eATP) to adenosine. After ischemia and CSVD, eATP is released from dying neurons as a damage molecule, triggering thrombosis and inflammation. In contrast, adenosine is anti-thrombotic, protects against oxidative stress, and suppresses the immune response. Evidently, therapies that promote adenosine generation or boost CD39 activity at the site of endothelial injury have promising benefits in the context of atherothrombotic stroke and can be extended to current CSVD known pathomechanisms. Here, we have reviewed the rationale and benefits of CD39 and CD39 therapies to treat endothelial dysfunction in the brain.

Physiology and Clinical Relevance of Enlarged Perivascular Spaces in the Aging Brain

Neurology ◽  
2021 ◽  
pp. 10.1212/WNL.0000000000013077
Author(s):  
Corey W Bown ◽  
Roxana O Carare ◽  
Matthew S Schrag ◽  
Angela L Jefferson
Keyword(s):  
Fluid Transport ◽  
Small Vessel Disease ◽  
Treatment Strategies ◽  
Small Vessel ◽  
Aging Brain ◽  
Perivascular Spaces ◽  
Vessel Disease ◽  
Clinical Consequences ◽  
The Brain

Perivascular spaces (PVS) are fluid filled compartments that are part of the cerebral blood vessel wall and represent the conduit for fluid transport in and out of the brain. PVS are considered pathologic when sufficiently enlarged to be visible on magnetic resonance imaging. Recent studies have demonstrated that enlarged PVS (ePVS) may have clinical consequences related to cognition. Emerging literature points to arterial stiffening and abnormal protein aggregation in vessel walls as two possible mechanisms that drive ePVS formation. In this review, we describe the clinical consequences, anatomy, fluid dynamics, physiology, risk factors, and in vivo quantification methods of ePVS. Given competing views of PVS physiology, we detail the two most prominent theoretical views and review ePVS associations with other common small vessel disease markers. As ePVS are a marker of small vessel disease and ePVS burden is higher in Alzheimer’s disease, a comprehensive understanding about ePVS is essential in developing prevention and treatment strategies.

scholarly journals Response to "Carotid Flow Augmentation as a Risk for Small Vessel Disease of the Brain"

2010 ◽  
Vol 23 (9) ◽  
pp. 933-933
Author(s):  
K. Kohara ◽  
N. Ochi ◽  
Y. Tabara ◽  
T. Miki
Keyword(s):  
Small Vessel Disease ◽  
Small Vessel ◽  
Vessel Disease ◽  
The Brain ◽  
Carotid Flow

scholarly journals Risk factors for small-vessel disease revealed by magnetic resonance imaging of the brain.

Nosotchu ◽  
1996 ◽  
Vol 18 (1) ◽  
pp. 10-18
Author(s):  
Tatsuo Kohriyama ◽  
Shinya Yamaguchi ◽  
Eiji Tanaka ◽  
Yasuhiro Yamamura ◽  
Shigenobu Nakamura
Keyword(s):  
Magnetic Resonance Imaging ◽  
Risk Factors ◽  
Magnetic Resonance ◽  
Small Vessel Disease ◽  
Small Vessel ◽  
Resonance Imaging ◽  
Vessel Disease ◽  
The Brain

scholarly journals Potassium channelopathy-like defect underlies early-stage cerebrovascular dysfunction in a genetic model of small vessel disease

2015 ◽  
Vol 112 (7) ◽  
pp. E796-E805 ◽  
Author(s):  
Fabrice Dabertrand ◽  
Christel Krøigaard ◽  
Adrian D. Bonev ◽  
Emmanuel Cognat ◽  
Thomas Dalsgaard ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Genetic Model ◽  
Small Vessel Disease ◽  
Early Stage ◽  
Mesenteric Arteries ◽  
Small Vessel ◽  
Pial Arteries ◽  
Vessel Disease ◽  
Myogenic Responses ◽  
The Brain

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), caused by dominant mutations in the NOTCH3 receptor in vascular smooth muscle, is a genetic paradigm of small vessel disease (SVD) of the brain. Recent studies using transgenic (Tg)Notch3R169C mice, a genetic model of CADASIL, revealed functional defects in cerebral (pial) arteries on the surface of the brain at an early stage of disease progression. Here, using parenchymal arterioles (PAs) from within the brain, we determined the molecular mechanism underlying the early functional deficits associated with this Notch3 mutation. At physiological pressure (40 mmHg), smooth muscle membrane potential depolarization and constriction to pressure (myogenic tone) were blunted in PAs from TgNotch3R169C mice. This effect was associated with an ∼60% increase in the number of voltage-gated potassium (KV) channels, which oppose pressure-induced depolarization. Inhibition of KV1 channels with 4-aminopyridine (4-AP) or treatment with the epidermal growth factor receptor agonist heparin-binding EGF (HB-EGF), which promotes KV1 channel endocytosis, reduced KV current density and restored myogenic responses in PAs from TgNotch3R169C mice, whereas pharmacological inhibition of other major vasodilatory influences had no effect. KV1 currents and myogenic responses were similarly altered in pial arteries from TgNotch3R169C mice, but not in mesenteric arteries. Interestingly, HB-EGF had no effect on mesenteric arteries, suggesting a possible mechanistic basis for the exclusive cerebrovascular manifestation of CADASIL. Collectively, our results indicate that increasing the number of KV1 channels in cerebral smooth muscle produces a mutant vascular phenotype akin to a channelopathy in a genetic model of SVD.

Small vessel disease

2020 ◽  
pp. 203-212
Author(s):  
Fergus N Doubal ◽  
Anna Poggesi ◽  
Leonardo Pantoni ◽  
Joanna M Wardlaw
Keyword(s):  
Small Vessel Disease ◽  
Current Knowledge ◽  
Intrinsic Disorder ◽  
Small Vessel ◽  
Imaging Features ◽  
World Region ◽  
Vessel Disease ◽  
Cerebral Arterioles ◽  
The Brain ◽  
Review Current

‘Small vessel disease’ describes a combination of neuroradiological and clinical features that are due to an intrinsic disorder of the small cerebral arterioles, capillaries, and venules in varying proportions. It is very common, usually sporadic, although rare monogenic forms are well described. The commonest presentations are with stroke or cognitive impairment. The cause of the small vessel abnormalities in the sporadic form is not well understood and the brain damage is generally attributed to ischaemia secondary to the vessel abnormality. However, evidence for altered microvessel function and blood brain barrier failure is accumulating. The commonest risk factors are increasing age, hypertension, smoking, and diabetes, but environmental and lifestyle factors are also important although poorly understood. Whether the imaging features or incidence of small vessel-related stroke or dementia vary by world region is unknown. We review current knowledge on presentation, aetiology, incidence, and prevalence of sporadic small vessel disease.

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