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Introduction: Cerebral amyloid angiopathy (CAA), the accumulation of amyloid- β (1-40) (A β ) around cerebral arteries, impairs endothelial function. Endothelium-dependent dilation is a consequence of transient increases in intracellular [Ca 2+ ] in endothelial cells (EC). The Ca 2+ permeable N-methyl-D-aspartate receptor (NMDAR) mediates endothelium-dependent dilation, although if these effects are dependent on Ca 2+ influx and transients, or if they are impaired by A β , remains undetermined. Hypothesis: A β inhibits endothelial NMDAR-mediated Ca 2+ influx and transients in murine pial arteries. Methods: We performed Ca 2+ time-lapse imaging of en face pial arteries from cdh5-GCaMP8 mice to quantify EC Ca 2+ events induced by NMDAR activation. Data are means ± SEM. Results: Elemental Ca 2+ entry through NMDAR, hereon called NMDAR sparklets , was assessed in arteries incubated with EGTA-AM and cyclopiazonic acid (CPA) to inhibit intracellular Ca 2+ transients. NMDA (10 μM) induced an increase in NMDAR sparklets frequency when compared to vehicle, an effect inhibited by the NMDAR antagonist D-APV (in Hz: 0.12±0.01 vs 0.44±0.05 vs 0.21±0.02, vehicle vs NMDA vs NMDA+D-APV, p2+ transients, also blocked by D-APV (in Hz: 0.24±0.05 vs 0.53±0.10 vs 0.28±0.05, vehicle vs NMDA vs NMDA+D-APV, pβ on Ca 2+ events in pial artery EC. We observed that 30 minutes exposure to A β (5 μM) caused a significant reduction in NMDAR sparklets (in Hz: 0.62±0.07 vs 0.22±0.03, NMDA vs NMDA + A β , p2+ transients (in Hz: 0.62±0.37 vs 0.27±0.07, NMDA vs NMDA + A β ). Lastly, we performed pressure myography on pial arteries of wild-type and 5x-FAD mice, a model of familial Alzheimer’s disease with rapid amyloid accumulation. 5x-FAD mice displayed impaired vasodilation to NMDA (vasodilation (%): 9.86±0.64 vs 4.22±2.76, wild-type vs 5x-FAD , p Conclusion: These preliminary data suggest that A β impairs endothelial NMDAR-associated Ca 2+ influx events in cerebral arteries, which can impair blood flow in CAA patients, thus contributing to cognitive impairment.

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 Ca2+ influx through L-type voltage-gated Ca2+ 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.

The incidence of obesity in the population is increasing at an alarming rate, with this comes an increased risk of insulin resistance (IR). Obesity and IR increase an individual's risk of having a stroke and they have been linked to several forms of dementia. Stroke and dementia are associated with, or exacerbated by, reduced cerebral blood flow, which has recently been described in obese patients. In this review we will discuss the effects of obesity on cerebral artery function and structure. Regarding their function, we will focus on the endothelium and nitric oxide (NO) dependent dilation. NO dependent dilation is impaired in cerebral arteries from obese rats, and the majority of evidence suggests this is a result of increased oxidative stress. We will also describe the limited studies showing that inward cerebral artery remodeling occurs in models of obesity, and that the remodeling is associated with an increase in the damage caused by cerebral ischemia. We will also discuss some of the more paradoxical findings associated with stroke and obesity, including the evidence that obesity is a positive factor for stroke survival. Finally we will discuss the evidence that links these changes in vascular structure and function to cognitive decline and dementia.

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.

Intracerebral parenchymal arterioles (PAs), which include parenchymal arterioles, penetrating arterioles and pre-capillary arterioles, are high resistance blood vessels branching out from pial arteries and arterioles and diving into the brain parenchyma. Individual PA perfuse a discrete cylindrical territory of the parenchyma and the neurons contained within. These arterioles are a central player in the regulation of cerebral blood flow both globally (cerebrovascular autoregulation) and locally (functional hyperemia). PAs are part of the neurovascular unit, a structure that matches regional blood flow to metabolic activity within the brain and also includes neurons, interneurons, and astrocytes. Perfusion through PAs is directly linked to the activity of neurons in that particular territory and increases in neuronal metabolism lead to an augmentation in local perfusion caused by dilation of the feed PA. Regulation of PAs differs from that of better-characterized pial arteries. Pressure-induced vasoconstriction is greater in PAs and vasodilatory mechanisms vary. In addition, PAs do not receive extrinsic innervation from perivascular nerves - innervation is intrinsic and indirect in nature through contact with astrocytic endfeet. Thus, data regarding contractile regulation accumulated by studies using pial arteries does not directly translate to understanding PA function. Further, it remains undetermined how pathological states, such as hypertension and diabetes, affect PA structure and reactivity. This knowledge gap is in part a consequence of the technical difficulties pertaining to PA isolation and cannulation. In this manuscript we present a protocol for isolation and cannulation of rodent PAs. Further, we show examples of experiments that can be performed with these arterioles, including agonist-induced constriction and myogenic reactivity. Although the focus of this manuscript is on PA cannulation and pressure myography, isolated PAs can also be used for biochemical, biophysical, molecular, and imaging studies.

Matrix metalloproteases (MMPs) are a family of zinc peptidases involved in extracellular matrix turnover. There is evidence that increased MMP activity is involved in remodeling of resistance vessels in chronic hypertension. Thus we hypothesized that inhibition of MMP activity with doxycycline (DOX) would attenuate vascular remodeling. Six-week-old male stroke-prone spontaneously hypertensive rats (SHRSP) were treated with DOX (50 mg·kg−1·day−1 in the drinking water) for 6 wk. Untreated SHRSP were controls. Blood pressure was measured by telemetry during the last week. Middle cerebral artery (MCA) and mesenteric resistance artery (MRA) passive structures were assessed by pressure myography. MMP-2 expression in aortas was measured by Western blot. All results are means ± SE. DOX caused a small increase in mean arterial pressure (SHRSP, 154 ± 1; SHRSP + DOX, 159 ± 3 mmHg; P < 0.001). Active MMP-2 expression was reduced in aorta from SHRSP + DOX (0.21 ± 0.06 vs. 0.49 ± 0.13 arbitrary units; P < 0.05). In the MCA, at 80 mmHg, DOX treatment increased the lumen (273.2 ± 4.7 vs. 238.3 ± 6.3 μm; P < 0.05) and the outer diameter (321 ± 5.3 vs. 290 ± 7.6 μm; P < 0.05) and reduced the wall-to-lumen ratio (0.09 ± 0.002 vs. 0.11 ± 0.003; P < 0.05). Damage after transient cerebral ischemia (transient MCA occlusion) was reduced in SHRSP + DOX (20.7 ± 4 vs. 45.5 ± 5% of hemisphere infarcted; P < 0.05). In the MRA, at 90 mmHg DOX, reduced wall thickness (29 ± 1 vs. 22 ± 1 μm; P < 0.001) and wall-to-lumen ratio (0.08 ± 0.004 vs. 0.11 ± 0.008; P < 0.05) without changing lumen diameter. These results suggest that MMPs are involved in hypertensive vascular remodeling in both the peripheral and cerebral vasculature and that DOX reduced brain damage after cerebral ischemia.

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.

Objective Chronic hypertension induces detrimental changes in the structure and function of surface cerebral arteries. Very little is known about parenchymal arterioles (PAs), which perfuse distinct neuronal populations in the cortex and may play a role in cerebrovascular disorders. We investigated the effect of deoxycorticosterone acetate (DOCA)-salt induced hypertension on endothelial function and artery structure in PAs and middle cerebral arteries (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

Careful regulation of cerebral blood flow is required to maintain proper brain function. The cerebral arteries are particularly sensitive to the effects of hypertension, which alters the arteries in a manner that impairs the brains ability to tightly regulate perfusion. This chapter focuses the effects of hypertension on cerebral artery structure and function, with emphasis on myogenic reactivity and endothelium-dependent dilation. Hypertension causes a reduction in the lumen diameter of cerebral arteries and this is often associated with an increase in the wall-to-lumen ratio. Several circulating factors have been implicated in mediating this inward artery remodeling; these include aldosterone, angiotensin II, proinflammatory cytokines, and reactive oxygen species. Endothelium-dependent dilation in response to nitric oxide and epoxyeicosatrienoic acids is impaired in hypertension; this leads to increases in myogenic tone and impaired dilation. Dysfunction of ion channels, including calcium-activated potassium channels and transient receptor potential (TRP) V4 channels, has also been associated with impaired endothelial function in hypertensive models. Understanding the mechanisms responsible for the hypertension-associated vascular dysfunction is important because hypertension is associated with an increased risk of dementia and stroke and with increased ischemic injury in the event of a stroke.

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.

Hypertension impairs neurovascular coupling, possibly by altering the structure and function of cerebral penetrating arterioles (PenA). We hypothesized that an antihypertensive therapy (AhT) would ...

Hypertension is linked to dementia in humans, as well as remodeling and dysfunction in large cerebral arteries. The effects of hypertension on cerebral microvessels, such as penetrating arterioles (PenA), are still unknown. These arterioles are the bottlenecks bridging the pial circulation to the deep parenchymal microcirculation, and they are vital for neurovascular coupling and functional hyperemia. Mineralocorticoid receptor (MR) antagonism reverses hypertension-induced changes in large cerebral arteries. Thus, we hypothesized that MR antagonism will improve PenA dilation and structure in adult rats with sustained hypertension. Twelve-week-old male stroke-prone spontaneously hypertensive rats (SHRSP) were treated with the MR antagonist eplerenone (EPL, 100mg/kg/day) or placebo for 6 weeks. PenA function and structure were studied by pressure myography. Data are means±SEM at 60mmHg intralumenal pressure, placebo vs EPL. Myogenic tone generation was not different between groups (%myogenic tone: 40.3±2.3 vs 41.3±2.0). PenA diameter after tone was higher in EPL (42.47±1.5 vs 49.21±2.4μm, p=0.02, t-test). Dilation of PenA to nifedipine (calcium channel blocker) was improved after EPL treatment, as evidenced by an increase in diameter change (10μM nifedipine: 13.44±1.94 vs 18.44±2.39μm, p

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.