Novel inductively coupled ear-bars (ICEs) to enhance restored fMRI signal from susceptibility compensation in rats.

Functional magnetic resonance imaging faces inherent challenges when applied to deep-brain areas in rodents, e.g. entorhinal cortex, due to the signal loss near the ear cavities induced by susceptibility artifacts and reduced sensitivity induced by the long distance from the surface array coil. Given the pivotal roles of deep brain regions in various diseases, optimized imaging techniques are needed. To mitigate susceptibility-induced signal losses, we introduced baby cream into the middle ear. To enhance the detection sensitivity of deep brain regions, we implemented inductively coupled ear-bars, resulting in approximately a 2-fold increase in sensitivity in entorhinal cortex. Notably, the inductively coupled ear-bar can be seamlessly integrated as an add-on device, without necessitating modifications to the scanner interface. To underscore the versatility of inductively coupled ear-bars, we conducted echo-planner imaging-based task functional magnetic resonance imaging in rats modeling Alzheimer's disease. As a proof of concept, we also demonstrated resting-state-functional magnetic resonance imaging connectivity maps originating from the left entorhinal cortex-a central hub for memory and navigation networks-to amygdala hippocampal area, Insular Cortex, Prelimbic Systems, Cingulate Cortex, Secondary Visual Cortex, and Motor Cortex. This work demonstrates an optimized procedure for acquiring large-scale networks emanating from a previously challenging seed region by conventional magnetic resonance imaging detectors, thereby facilitating improved observation of functional magnetic resonance imaging outcomes.

Female mice are protected from impaired parenchymal arteriolar TRPV4 function and impaired cognition in hypertension.

Hypertension is a leading modifiable risk factor for cerebral small vessel disease. Our laboratory has shown that endothelium-dependent dilation in cerebral parenchymal arterioles (PAs) is dependent on transient receptor potential vanilloid 4 (TRPV4) activation, and this pathway is impaired in hypertension. This impaired dilation is associated with cognitive deficits and neuroinflammation. Epidemiological evidence suggests that women with midlife hypertension have an increased dementia risk that does not exist in age-matched men, though the mechanisms responsible for this are unclear. This study aimed to determine the sex differences in young, hypertensive mice to serve as a foundation for future determination of sex differences at midlife. We tested the hypothesis that young hypertensive female mice would be protected from the impaired TRPV4-mediated PA dilation and cognitive dysfunction observed in male mice. Angiotensin II (ANG II)-filled osmotic minipumps (800 ng/kg/min, 4 wk) were implanted in 16- to 19-wk-old male C56BL/6 mice. Age-matched female mice received either 800 ng/kg/min or 1,200 ng/kg/min ANG II. Sham-operated mice served as controls. Systolic blood pressure was elevated in ANG II-treated male mice and in 1,200 ng ANG II-treated female mice versus sex-matched shams. PA dilation in response to the TRPV4 agonist GSK1016790A (10-9-10-5 M) was impaired in hypertensive male mice, which was associated with cognitive dysfunction and neuroinflammation, reproducing our previous findings. Hypertensive female mice exhibited normal TRPV4-mediated PA dilation and were cognitively intact. Female mice also showed fewer signs of neuroinflammation than male mice. Determining the sex differences in cerebrovascular health in hypertension is critical for developing effective therapeutic strategies for women.NEW & NOTEWORTHY Vascular dementia is a significant public health concern, and the effect of biological sex on dementia development is not well understood. TRPV4 channels are essential regulators of cerebral parenchymal arteriolar function and cognition. Hypertension impairs TRPV4-mediated dilation and memory in male rodents. Data presented here suggest female sex protects against impaired TRPV4 dilation and cognitive dysfunction during hypertension. These data advance our understanding of the influence of biological sex on cerebrovascular health in hypertension.

Chronic cerebral hypoperfusion in male rats results in sustained HPA activation and hyperinsulinemia.

Vascular contributions to cognitive impairment and dementia (VCID) is a spectrum of cognitive deficits caused by cerebrovascular disease, for which insulin resistance is a major risk factor. A major cause of VCID is chronic cerebral hypoperfusion (CCH). Under stress, sustained hypothalamic-pituitary-adrenal axis (HPA) activation can result in insulin resistance. Little is known about the effects of CCH on the HPA axis. We hypothesized that CCH causes sustained HPA activation and insulin resistance. Male rats were subjected to bilateral carotid artery stenosis (BCAS) for 12 wk to induce CCH and VCID. BCAS reduced cerebral blood flow and caused memory impairment. Plasma adrenocorticotropic hormone was increased in the BCAS rats (117.2 ± 9.6 vs. 88.29 ± 9.1 pg/mL, BCAS vs. sham, P = 0.0236), as was corticosterone (220 ± 21 vs. 146 ± 18 ng/g feces, BCAS vs. sham, P = 0.0083). BCAS rats were hypoglycemic (68.1 ± 6.1 vs. 76.5 ± 5.9 mg/dL, BCAS vs. sham, P = 0.0072), with increased fasting insulin (481.6 ± 242.6 vs. 97.94 ± 40.02 pmol/L, BCAS vs. sham, P = 0.0003) indicating that BCAS rats were insulin resistant [homeostasis model assessment of ß-cell function-insulin resistance (HOMA-IR): 11.71 ± 6.47 vs. 2.62 ± 0.93; BCAS vs. control, P = 0.0008]. Glucose tolerance tests revealed that BCAS rats had lower blood glucose areas under the curve (AUCs) than controls (250 ± 12 vs. 326 ± 20 mg/dL/h, BCAS vs. sham, P = 0.0075). These studies indicate that CCH causes sustained activation of the HPA and results in insulin resistance, a condition that is expected to worsen VCID.NEW & NOTEWORTHY Cerebrovascular disease and insulin resistance are two major risk factors for the development of dementia. Here, we demonstrate that chronic cerebral hypoperfusion results in glucocorticoid excess and hyperinsulinemia. This study indicates that chronic cerebral hypoperfusion, glucocorticoid excess, and insulin resistance participate in a detrimental cycle that could exacerbate cerebral vascular disease and dementia.

Soluble epoxide hydrolase inhibition improves cognitive function and parenchymal artery dilation in a hypertensive model of chronic cerebral hypoperfusion.

OBJECTIVE: Parenchymal arterioles (PAs) regulate perfusion of the cerebral microcirculation, and impaired PA endothelium-dependent dilation occurs in dementia models mimicking chronic cerebral hypoperfusion (CCH). Epoxyeicosatrienoic acids (EETs) are vasodilators; their actions are potentiated by soluble epoxide hydrolase (sEH) inhibition. We hypothesized that chronic sEH inhibition with trifluoromethoxyphenyl-3 (1-propionylpiperidin-4-yl) urea (TPPU) would prevent cognitive dysfunction and improve PA dilation in a hypertensive CCH model. METHODS: Bilateral carotid artery stenosis (BCAS) was used to induce CCH in twenty-week-old male stroke-prone spontaneously hypertensive rats (SHSRP) that were treated with vehicle or TPPU for 8 weeks. Cognitive function was assessed by novel object recognition. PA dilation and structure were assessed by pressure myography, and mRNA expression in brain tissue was assessed by qRT-PCR. RESULTS: TPPU did not enhance resting cerebral perfusion, but prevented CCH-induced memory deficits. TPPU improved PA endothelium-dependent dilation but reduced the sensitivity of PAs to a nitric oxide donor. TPPU treatment had no effect on PA structure or biomechanical properties. TPPU treatment increased brain mRNA expression of brain derived neurotrophic factor, doublecortin, tumor necrosis factor-alpha, sEH, and superoxide dismutase 3, CONCLUSIONS: These data suggest that sEH inhibitors may be viable treatments for cognitive impairments associated with hypertension and CCH.

Regulation of ion channels in the microcirculation by mineralocorticoid receptor activation.

The mineralocorticoid receptor (MR) has classically been studied in the renal epithelium for its role in regulating sodium and water balance and, subsequently, blood pressure. However, the MR also plays a critical role in the microvasculature by regulating ion channel expression and function. Activation of the MR by its endogenous agonist aldosterone results in translocation of the MR into the nucleus, where it can act as a transcription factor. Although most of the actions of the aldosterone can be attributed to its genomic activity though MR activation, it can also act by nongenomic mechanisms. Activation of this ubiquitous receptor increases the expression of epithelial sodium channels (ENaC) in both the endothelium and smooth muscle cells of peripheral and cerebral vessels. MR activation also regulates activity of calcium channels, calcium-activated potassium channels, and various transient receptor potential (TRP) channels. Modification of these ion channels results in a myriad of negative consequences, including impaired endothelium-dependent vasodilation, alterations in generation of myogenic tone, and increased inflammation and oxidative stress. Taken together, these studies demonstrate the importance of studying the impact of the MR on ion channel function in the vasculature. While research in this area has made advances in recent years, there are still many large gaps in knowledge that need to be filled. Crucial future directions of study include defining the molecular mechanisms involved in this interaction, as well as elucidating the potential sex differences that may exist, as these areas of understanding are currently lacking.

Rs10230207 genotype confers changes in HDAC9 and TWIST1, but not FERD3L in lymphoblasts from patients with intracranial aneurysm.

Intracranial aneurysms (IA) are weakened outpouchings of the arterial wall in the cerebrovasculature. Rupture of an IA often leads to devastating consequences. The early identification of IA patients is crucial for management of their condition. A genetic variant at rs10230207, located nearby the HDAC9, TWIST1, and FERD3L genes, is associated with IA. HDAC9 is a class IIa histone deacetylase that mediates vascular smooth muscle cell dysfunction. TWIST1 is a mechanosensitive transcription factor and its expression is reduced in unstable carotid atherosclerotic plaques. In this study, the expression of the HDAC9, TWIST1, and FERD3L genes was characterized and associated with the presence of the rs10230207 genetic variant. Allelic discrimination and gene expression analysis were performed using lymphoblasts from 85 population controls and 109 IA patients. Subjects that were heterozygous (GT) within rs10230207 were 4.32 times more likely to have an IA than those that were homozygous for the reference allele (GG; 95%CI 1.23 to 14.16). Subjects that were homozygous (TT) were 8.27 times more likely to have an IA than those that were GG (95%CI 2.45 to 27.85). While the presence of the risk allele was not associated with changes in FERD3L gene expression, the risk allele was associated with increased HDAC9 and decrease in TWIST1 mRNA expression. The significant inverse correlation between HDAC9 and TWIST1 gene expression suggests that changes in the expression of both of genes may contribute to the formation of IAs.

Transient receptor potential vanilloid 4 channels are important regulators of parenchymal arteriole dilation and cognitive function.

OBJECTIVE: Hypertension-associated PA dysfunction reduces cerebral perfusion and impairs cognition. This is associated with impaired TRPV4-mediated PA dilation; therefore, we tested the hypothesis that TRPV4 channels are important regulators of cerebral perfusion, PA structure and dilation, and cognition. METHODS: Ten- to twelve-month-old male TRPV4 knockout (WKY-Trpv4em4Mcwi ) and age-matched control WKY rats were studied. Cerebral perfusion was measured by MRI with arterial spin labeling. PA structure and function were assessed using pressure myography and cognitive function using the novel object recognition test. RESULTS: Cerebral perfusion was reduced in the WKY-Trpv4em4Mcwi rats. This was not a result of PA remodeling because TRPV4 deletion did not change PA structure. TRPV4 deletion did not change PA myogenic tone development, but PAs from the WKY-Trpv4em4Mcwi rats had severely blunted endothelium-dependent dilation. The WKY-Trpv4em4Mcwi rats had impaired cognitive function and exhibited depressive-like behavior. The WKY-Trpv4em4Mcwi rats also had increased microglia activation, and increased mRNA expression of GFAP and tumor necrosis factor alpha suggesting increased inflammation. CONCLUSION: Our data indicate that TRPV4 channels play a critical role in cerebral perfusion, PA dilation, cognition, and inflammation. Impaired TRPV4 function in diseases such as hypertension may increase the risk of the development of vascular dementia.

Carotid artery stenosis in hypertensive rats impairs dilatory pathways in parenchymal arterioles.

Hypertension is a leading risk factor for vascular cognitive impairment and is strongly associated with carotid artery stenosis. In normotensive rats, chronic cerebral hypoperfusion induced by bilateral common carotid artery stenosis (BCAS) leads to cognitive impairment that is associated with impaired endothelium-dependent dilation in parenchymal arterioles (PAs). The aim of this study was to assess the effects of BCAS on PA function and structure in stroke-prone spontaneously hypertensive rats, a model of human essential hypertension. Understanding the effects of hypoperfusion on PAs in a hypertensive model could lead to the identification of therapeutic targets for cognitive decline in a model that reflects the at-risk population. We hypothesized that BCAS would impair endothelium-dependent dilation in PAs and induce artery remodeling compared with sham rats. PAs from BCAS rats had endothelial dysfunction, as assessed using pressure myography. Inhibition of nitric oxide and prostaglandin production had no effect on PA dilation in sham or BCAS rats. Surprisingly, inhibition of epoxyeicosatrienoic acid production increased dilation in PAs from BCAS rats but not from sham rats. Similar results were observed in the presence of inhibitors for all three dilatory pathways, suggesting that epoxygenase inhibition may have restored a nitric oxide/prostaglandin-independent dilatory pathway in PAs from BCAS rats. PAs from BCAS rats underwent remodeling with a reduced wall thickness. These data suggest that marked endothelial dysfunction in PAs from stroke-prone spontaneously hypertensive rats with BCAS may be associated with the development of vascular cognitive impairment. NEW & NOTEWORTHY The present study assessed the structure and function of parenchymal arterioles in a model of chronic cerebral hypoperfusion and hypertension, both of which are risk factors for cognitive impairment. We observed that impaired dilation and artery remodeling in parenchymal arterioles and abolished cerebrovascular reserve capacity may mediate cognitive deficits.

Mineralocorticoid receptor antagonism improves parenchymal arteriole dilation via a TRPV4-dependent mechanism and prevents cognitive dysfunction in hypertension.

Hypertension and mineralocorticoid receptor activation cause cerebral parenchymal arteriole remodeling; this can limit cerebral perfusion and contribute to cognitive dysfunction. We used a mouse model of angiotensin II-induced hypertension to test the hypothesis that mineralocorticoid receptor activation impairs both transient receptor potential vanilloid (TRPV)4-mediated dilation of cerebral parenchymal arterioles and cognitive function. Mice (16-18 wk old, male, C57Bl/6) were treated with angiotensin II (800 ng·kg-1·min-1) with or without the mineralocorticoid receptor antagonist eplerenone (100 mg·kg-1·day-1) for 4 wk; sham mice served as controls. Data are presented as means ± SE; n = 5-14 mice/group. Eplerenone prevented the increased parenchymal arteriole myogenic tone and impaired carbachol-induced (10-9-10-5 mol/l) dilation observed during hypertension. The carbachol-induced dilation was endothelium-derived hyperpolarization mediated because it could not be blocked by N-nitro-l-arginine methyl ester (10-5 mol/l) and indomethacin (10-4 mol/l). We used GSK2193874 (10-7 mol/l) to confirm that in all groups this dilation was dependent on TRPV4 activation. Dilation in response to the TRPV4 agonist GSK1016790A (10-9-10-5 mol/l) was also reduced in hypertensive mice, and this defect was corrected by eplerenone. In hypertensive and eplerenone-treated animals, TRPV4 inhibition reduced myogenic tone, an effect that was not observed in arterioles from control animals. Eplerenone treatment also improved cognitive function and reduced microglia density in hypertensive mice. These data suggest that the mineralocorticoid receptor is a potential therapeutic target to improve cerebrovascular function and cognition during hypertension. NEW & NOTEWORTHY Vascular dementia is a growing public health issue that lacks effective treatments. Transient receptor potential vanilloid (TRPV)4 channels are important regulators of parenchymal arteriole dilation, and they modulate myogenic tone. The data presented here suggest that TRPV4 channel expression is regulated by the mineralocorticoid receptor (MR). MR blockade also improves cognitive function during hypertension. MR blockade might be a potential therapeutic approach to improve cerebrovascular function and cognition in patients with hypertension.

Mineralocorticoid receptor antagonism prevents obesity-induced cerebral artery remodeling and reduces white matter injury in rats.

OBJECTIVE: Midlife obesity is a risk factor for dementia development. Obesity has also been linked to hyperaldosteronism, and this can be modeled in rats by high fat (HF) feeding from weaning. Aldosterone, or activation of the mineralocorticoid receptor (MR) causes cerebrovascular injury in lean hypertensive rats. We hypothesized that rats fed a HF diet would show inward middle cerebral artery (MCA) remodeling that could be prevented by MR antagonism. We further proposed that the cerebral artery remodeling would be associated with white mater injury. METHODS: Three-week-old male Sprague-Dawley rats were fed a HF diet ± the MR antagonist canrenoic acid (Canr) for 17 weeks. Control rats received normal chow (control NC). MCA structure was assessed by pressure myography. RESULTS: The MCAs from HF fed rats had smaller lumens and thicker walls when compared to arteries from control NC rats; Canr prevented the MCA remodeling associated with HF feeding. HF feeding increased the mRNA expression of markers of cell proliferation and vascular inflammation in cerebral arteries and Canr treatment prevented this. White mater injury was increased in the rats fed the HF diet and this was reduced by Canr treatment. The expression of doublecortin, a marker of new and immature neurons was reduced in HF fed rats, and MR antagonism normalized this. CONCLUSIONS: These data suggest that HF feeding leads to MR dependent remodeling of the MCA and this is associated with markers of dementia development.

Bilateral common carotid artery stenosis in normotensive rats impairs endothelium-dependent dilation of parenchymal arterioles.

Chronic cerebral hypoperfusion is a risk factor for cognitive impairment. Reduced blood flow through the common carotid arteries induced by bilateral carotid artery stenosis (BCAS) is a physiologically relevant model of chronic cerebral hypoperfusion. We hypothesized that BCAS in 20-wk-old Wistar-Kyoto (WKY) rats would impair cognitive function and lead to reduced endothelium-dependent dilation and outward remodeling in the parenchymal arterioles (PAs). After 8 wk of BCAS, both short-term memory and spatial discrimination abilities were impaired. In vivo assessment of cerebrovascular reserve capacity showed a severe impairment after BCAS. PA endothelial function and structure were assessed by pressure myography. BCAS impaired endothelial function in PAs, as evidenced by reduced dilation to carbachol. Addition of nitric oxide synthase and cyclooxygenase inhibitors did not change carbachol-mediated dilation in either group. Inhibiting CYP epoxygenase, the enzyme that produces epoxyeicosatrienoic acid (EETs), a key determinant of endothelium-derived hyperpolarizing factor (EDHF)-mediated dilation, abolished dilation in PAs from Sham rats, but had no effect in PAs from BCAS rats. Expression of TRPV4 channels, a target for EETs, was decreased and maximal dilation to a TRPV4 agonist was attenuated after BCAS. Together these data suggest that EET-mediated dilation is impaired in PAs after BCAS. Thus impaired endothelium-dependent dilation in the PAs may be one of the contributing factors to the cognitive impairment observed after BCAS.

Aging is associated with changes to the biomechanical properties of the posterior cerebral artery and parenchymal arterioles.

Artery remodeling, described as a change in artery structure, may be responsible for the increased risk of cardiovascular disease with aging. Although the risk for stroke is known to increase with age, relatively young animals have been used in most stroke studies. Therefore, more information is needed on how aging alters the biomechanical properties of cerebral arteries. Posterior cerebral arteries (PCAs) and parenchymal arterioles (PAs) are important in controlling brain perfusion. We hypothesized that aged (22-24 mo old) C57bl/6 mice would have stiffer PCAs and PAs than young (3-5 mo old) mice. The biomechanical properties of the PCAs and PAs were assessed by pressure myography. Data are presented as means ± SE of young vs. old. In the PCA, older mice had increased outer (155.6 ± 3.2 vs. 169.9 ± 3.2 µm) and lumen (116.4 ± 3.6 vs. 137.1 ± 4.7 µm) diameters. Wall stress (375.6 ± 35.4 vs. 504.7 ± 60.0 dyn/cm(2)) and artery stiffness (ß-coefficient: 5.2 ± 0.3 vs. 7.6 ± 0.9) were also increased. However, wall strain (0.8 ± 0.1 vs. 0.6 ± 0.1) was reduced with age. In the PAs from old mice, wall thickness (3.9 ± 0.3 vs. 5.1 ± 0.2 µm) and area (591.1 ± 95.4 vs. 852.8 ± 100 µm(2)) were increased while stress (758.1 ± 100.0 vs. 587.2 ± 35.1 dyn/cm(2)) was reduced. Aging also increased mean arterial and pulse pressures. We conclude that age-associated remodeling occurs in large cerebral arteries and arterioles and may increase the risk of cerebrovascular disease.

DOCA-salt hypertension impairs artery function in rat middle cerebral artery and parenchymal arterioles.

OBJECTIVE: Chronic hypertension induces detrimental changes in the structure and function of surface cerebral arteries. Very little is known about PAs, which perfuse distinct neuronal populations in the cortex and may play a role in cerebrovascular disorders. We investigated the effect of DOCA-salt induced hypertension on endothelial function and artery structure in PAs and MCAs. METHODS: Uninephrectomized male Sprague-Dawley rats were implanted with a subcutaneous pellet containing DOCA (150 mg/kg b.w.) and drank salt water (1% NaCl and 0.2% KCl) for 4 weeks. Sham rats were uninephrectomized and drank tap water. Vasoreactivity and passive structure in the MCAs and the PAs were assessed by pressure myography. RESULTS: Both MCAs and PAs from DOCA-salt rats exhibited impaired endothelium-dependent dilation (P<.05). In the PAs, addition of NO and COX inhibitors enhanced dilation in DOCA-salt rats (P<.05), suggesting that dysfunctional NO and COX-dependent signaling could contribute to impaired endothelium-mediated dilation. MCAs from DOCA-salt rats exhibited inward remodeling (P<.05). CONCLUSIONS: Hypertension-induced MCA remodeling coupled with impaired endothelium-dependent dilation in both the MCAs and PAs may exacerbate the risk of cerebrovascular accidents and the associated morbidity and mortality.

Regulation of myogenic tone and structure of parenchymal arterioles by hypertension and the mineralocorticoid receptor.

Proper perfusion is vital for maintenance of neuronal homeostasis and brain function. Changes in the function and structure of cerebral parenchymal arterioles (PAs) could impair blood flow regulation and increase the risk of cerebrovascular diseases, including dementia and stroke. Hypertension alters the structure and function of large cerebral arteries, but its effects on PAs remain unknown. We hypothesized that hypertension increases myogenic tone and induces inward remodeling in PAs; we further proposed that antihypertensive therapy or mineralocorticoid receptor (MR) blockade would reverse the effects of hypertension. PAs from 18-wk-old stroke-prone spontaneously hypertensive rats (SHRSP) were isolated and cannulated in a pressure myograph. At 50-mmHg intraluminal pressure, PAs from SHRSP showed higher myogenic tone (%tone: 39.1 ± 1.9 vs. 28.7 ± 2.5%, P < 0.01) and smaller resting luminal diameter (34.7 ± 1.9 vs. 46.2 ± 2.4 µm, P < 0.01) than those from normotensive Wistar-Kyoto rats, through a mechanism that seems to require Ca(2+) influx through L-type voltage-gated Ca(2+) channels. PAs from SHRSP showed inward remodeling (luminal diameter at 60 mmHg: 55.2 ± 1.4 vs. 75.7 ± 5.1 µm, P < 0.01) and a paradoxical increase in distensibility and compliance. Treatment of SHRSP for 6 wk with antihypertensive therapy reduced PAs' myogenic tone, increased their resting luminal diameter, and prevented inward remodeling. In contrast, treatment of SHRSP for 6 wk with an MR antagonist did not reduce blood pressure or myogenic tone, but prevented inward remodeling. Thus, while hypertensive remodeling of PAs may involve the MR, myogenic tone seems to be independent of MR activity.

Tumor necrosis factor-α inhibition attenuates middle cerebral artery remodeling but increases cerebral ischemic damage in hypertensive rats.

Hypertension causes vascular inflammation evidenced by an increase in perivascular macrophages and proinflammatory cytokines in the arterial wall. Perivascular macrophage depletion reduced tumor necrosis factor (TNF)-α expression in cerebral arteries of hypertensive rats and attenuated inward remodeling, suggesting that TNF-α might play a role in the remodeling process. We hypothesized that TNF-α inhibition would improve middle cerebral artery (MCA) structure and reduce damage after cerebral ischemia in hypertensive rats. Six-week-old male stroke-prone spontaneously hypertensive rats (SHRSP) were treated with the TNF-α inhibitor etanercept (ETN; 1.25 mg·kg(-1)·day(-1) ip daily) or PBS (equivolume) for 6 wk. The myogenic tone generation, postischemic dilation, and passive structure of MCAs were assessed by pressure myography. Cerebral ischemia was induced by MCA occlusion (MCAO). Myogenic tone was unchanged, but MCAs from SHRSP + ETN had larger passive lumen diameter and reduced wall thickness and wall-to-lumen ratio. Cerebral infarct size was increased in SHRSP + ETN after transient MCAO, despite an improvement in dilation of nonischemic MCA. The increase in infarct size was linked to a reduction in the number of microglia in the infarct core and upregulation of markers of classical macrophage/microglia polarization. There was no difference in infarct size after permanent MCAO or when untreated SHRSP subjected to transient MCAO were given ETN at reperfusion. Our data suggests that TNF-α inhibition attenuates hypertensive MCA remodeling but exacerbates cerebral damage following ischemia/reperfusion injury likely due to inhibition of the innate immune response of the brain.

Chemerin connects fat to arterial contraction.

OBJECTIVE: Obesity and hypertension are comorbid in epidemic proportion, yet their biological connection is largely a mystery. The peptide chemerin is a candidate for connecting fat deposits around the blood vessel (perivascular adipose tissue) to arterial contraction. We presently tested the hypothesis that chemerin is expressed in perivascular adipose tissue and is vasoactive, supporting the existence of a chemerin axis in the vasculature. APPROACH AND RESULTS: Real-time polymerase chain reaction, immunohistochemistry, and Western analyses supported the synthesis and expression of chemerin in perivascular adipose tissue, whereas the primary chemerin receptor ChemR23 was expressed both in the tunica media and endothelial layer. The ChemR23 agonist chemerin-9 caused receptor, concentration-dependent contraction in the isolated rat thoracic aorta, superior mesenteric artery, and mesenteric resistance artery, and contraction was significantly amplified (more than 100%) when nitric oxide synthase was inhibited and the endothelial cell mechanically removed or tone was placed on the arteries. The novel ChemR23 antagonist CCX832 inhibited phenylephrine-induced and prostaglandin F2α-induced contraction (+perivascular adipose tissue), suggesting that endogenous chemerin contributes to contraction. Arteries from animals with dysfunctional endothelium (obese or hypertensive) demonstrated a pronounced contraction to chemerin-9. Finally, mesenteric arteries from obese humans demonstrate amplified contraction to chemerin-9. CONCLUSIONS: These data support a new role for chemerin as an endogenous vasoconstrictor that operates through a receptor typically attributed to function only in immune cells.

The effects of hypertension on the cerebral circulation.

Maintenance of brain function depends on a constant blood supply. Deficits in cerebral blood flow are linked to cognitive decline, and they have detrimental effects on the outcome of ischemia. Hypertension causes alterations in cerebral artery structure and function that can impair blood flow, particularly during an ischemic insult or during periods of low arterial pressure. This review will focus on the historical discoveries, novel developments, and knowledge gaps in 1) hypertensive cerebral artery remodeling, 2) vascular function with emphasis on myogenic reactivity and endothelium-dependent dilation, and 3) blood-brain barrier function. Hypertensive artery remodeling results in reduction in the lumen diameter and an increase in the wall-to-lumen ratio in most cerebral arteries; this is linked to reduced blood flow postischemia and increased ischemic damage. Many factors that are increased in hypertension stimulate remodeling; these include the renin-angiotensin-aldosterone system and reactive oxygen species levels. Endothelial function, vital for endothelium-mediated dilation and regulation of myogenic reactivity, is impaired in hypertension. This is a consequence of alterations in vasodilator mechanisms involving nitric oxide, epoxyeicosatrienoic acids, and ion channels, including calcium-activated potassium channels and transient receptor potential vanilloid channel 4. Hypertension causes blood-brain barrier breakdown by mechanisms involving inflammation, oxidative stress, and vasoactive circulating molecules. This exposes neurons to cytotoxic molecules, leading to neuronal loss, cognitive decline, and impaired recovery from ischemia. As the population ages and the incidence of hypertension, stroke, and dementia increases, it is imperative that we gain a better understanding of the control of cerebral artery function in health and disease.

Improvement in middle cerebral artery structure and endothelial function in stroke-prone spontaneously hypertensive rats after macrophage depletion.

BACKGROUND: Inflammation is involved in the pathogenesis of hypertension. Hypertensive animals have an increased number of perivascular macrophages in cerebral arteries. Macrophages might be involved in remodeling of the cerebral vasculature. We hypothesized that peripheral macrophage depletion would improve MCA structure and function in hypertensive rats. METHODS: For macrophage depletion, six-week-old stroke-prone spontaneously hypertensive rats (SHRSP) were treated with CLOD, 10 mL/kg every three or four days, i.p., or vehicle (PBS lipo). MCA structure and function were analyzed by pressure and wire myography. RESULTS: Blood pressure was not affected by CLOD. The number of perivascular CD163-positive cells per microscopic field was reduced in the brain of SHRSP+CLOD. CLOD treatment caused an improvement in endothelium-dependent dilation after intralumenal perfusion of ADP and incubation with Ach. Inhibition of NO production blunted the Ach response, and endothelium-independent dilation was not altered. At an intralumenal pressure of 80 mmHg, MCA from SHRSP+CLOD showed increased lumen diameter, decreased wall thickness, and wall-to-lumen ratio. Cross-sectional area of pial arterioles from SHRSP+CLOD was higher than PBS lipo. CONCLUSIONS: These results suggest that macrophage depletion attenuates MCA remodeling and improves MCA endothelial function in SHRSP.

Effects of Striatal Amyloidosis on the Dopaminergic System and Behavior: A Comparative Study in Male and Female 5XFAD Mice.

BACKGROUND: Nearly two-thirds of patients diagnosed with Alzheimer's disease (AD) are female. In addition, female patients with AD have more significant cognitive impairment than males at the same disease stage. This disparity suggests there are sex differences in AD progression. While females appear to be more affected by AD, most published behavioral studies utilize male mice. In humans, there is an association between antecedent attention-deficit/hyperactivity disorder and increased risk of dementia. Functional connectivity studies indicate that dysfunctional cortico-striatal networks contribute to hyperactivity in attention deficit hyperactivity disorder. Higher plaque density in the striatum accurately predicts the presence of clinical AD pathology. In addition, there is a link between AD-related memory dysfunction and dysfunctional dopamine signaling. OBJECTIVE: With the need to consider sex as a biological variable, we investigated the influence of sex on striatal plaque burden, dopaminergic signaling, and behavior in prodromal 5XFAD mice. METHODS: Six-month-old male and female 5XFAD and C57BL/6J mice were evaluated for striatal amyloid plaque burden, locomotive behavior, and changes in dopaminergic machinery in the striatum. RESULTS: 5XFAD female mice had a higher striatal amyloid plaque burden than male 5XFAD mice. 5XFAD females, but not males, were hyperactive. Hyperactivity in female 5XFAD mice was associated with increased striatal plaque burden and changes in dopamine signaling in the dorsal striatum. CONCLUSION: Our results indicate that the progression of amyloidosis involves the striatum in females to a greater extent than in males. These studies have significant implications for using male-only cohorts in the study of AD progression.

Vascular and Nonvascular Mechanisms of Cognitive Impairment and Dementia.

Aging, familial gene mutations, and genetic, environmental, and modifiable lifestyle risk factors predispose individuals to cognitive impairment or dementia by influencing the efficacy of multiple, often interdependent cellular and molecular homeostatic pathways mediating neuronal, glial, and vascular integrity and, ultimately, cognitive status. This review summarizes data from foundational and recent breakthrough studies to highlight common and differential vascular and nonvascular pathogenic mechanisms underlying the progression of Alzheimer disease, vascular dementia, frontotemporal dementia, and dementia with Lewy bodies.