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 middle cerebral artery (MCA) structure and function in hypertensive rats. Methods for macrophage depletion, six-week-old stroke-prone spontaneously hypertensive rats (SHRSP) were treated with liposome-encapsulated clodronate (CLOD, 10ml/kg/every 3 or 4 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 acetylcholine (Ach). Inhibition of nitric oxide 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. Conclusion These results suggest that macrophage depletion attenuates MCA remodeling and improves MCA endothelial function in SHRSP.

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.

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Background: A 25-base pair (25bp) intronic deletion in the MYBPC3 gene enriched in South Asians (SAs) is a risk allele for late-onset left ventricular (LV) dysfunction, hypertrophy, and heart failure (HF) with several forms of cardiomyopathy. However, the effect of this variant on exercise parameters has not been evaluated.Methods: As a pilot study, 10 asymptomatic SA carriers of the MYBPC3Δ25bp variant (52.9 ± 2.14 years) and 10 age- and gender-matched non-carriers (NCs) (50.1 ± 2.7 years) were evaluated at baseline and under exercise stress conditions using bicycle exercise echocardiography and continuous cardiac monitoring.Results: Baseline echocardiography parameters were not different between the two groups. However, in response to exercise stress, the carriers of Δ25bp had significantly higher LV ejection fraction (%) (CI: 4.57 ± 1.93; p < 0.0001), LV outflow tract peak velocity (m/s) (CI: 0.19 ± 0.07; p < 0.0001), and higher aortic valve (AV) peak velocity (m/s) (CI: 0.103 ± 0.08; p = 0.01) in comparison to NCs, and E/A ratio, a marker of diastolic compliance, was significantly lower in Δ25bp carriers (CI: 0.107 ± 0.102; p = 0.038). Interestingly, LV end-diastolic diameter (LVIDdia) was augmented in NCs in response to stress, while it did not increase in Δ25bp carriers (CI: 0.239 ± 0.125; p = 0.0002). Further, stress-induced right ventricular systolic excursion velocity s' (m/s), as a marker of right ventricle function, increased similarly in both groups, but tricuspid annular plane systolic excursion increased more in carriers (slope: 0.008; p = 0.0001), suggesting right ventricle functional differences between the two groups.Conclusions: These data support that MYBPC3Δ25bp is associated with LV hypercontraction under stress conditions with evidence of diastolic impairment.

Middle cerebral artery (MCA) occlusion (MCAO) causes endothelial dysfunction in the ischemic MCA (Marrelli et al., AJP 276:H33‐H41), and in small mesenteric arteries (Martinez‐Revelles et al., JPET 325: 363–9). The effect of MCAO on the contralateral MCA (CL MCA) however is unknown. In hypertensive rats MCA remodeling impairs artery function, and etanercept (ETN) attenuates this. We hypothesized that CL MCA dilation is impaired after MCAO and that ETN will improve this. 12 week old stroke prone spontaneously hypertensive rats, ETN‐treated from 6 weeks of age (ETN IR) or untreated (IR), underwent 1 hour of MCAO and 47 hours reperfusion. SHAM controls were generated. Cerebral blood flow (CBF) was measured by laser Doppler flowmetry. CL MCAs were mounted in a pressure myograph under physiological conditions. Endothelial function was assessed by intraluminal perfusion of ADP. Data are presented as mean ± SEM. Tone generation was not different between the groups. ADP mediated dilation was impaired in the IR group and this was ameliorated by ETN treatment (p<0.05). This caused a small, but insignificant (p=0.12), increase in post‐MCAO CBF in the ETN IR group. Our data suggest that ETN improves CL MCA endothelial function and may improve post‐MCAO CBF in hypertensive rats. (AHA0840122N) SHAM (n=2) ETN IR (n=3) IR (n=4) Tone (%) 32.6±5.4 33.2±7.1 36.9±4.7 Maximum increase in lumen diameter with ADP (μm) 62.5±12.5 60.6±7.5 28.2±7.8 Flow (% of pre‐MCAO) 94.5±10.9 86.6±7.0 62.6±10.1

Hypertension increases macrophages (MΦ) around the cerebral arteries. These MΦ may release mediators that could modulate endothelial function. We hypothesized that MΦ depletion would improve middle cerebral artery (MCA) endothelial function in stroke‐prone spontaneously hypertensive rats (SHRSP). Liposome‐encapsulated clodronate (CLOD) was used to deplete MΦ, control rats received PBS containing liposomes; rats were treated from 6–12 weeks of age. Data are mean±SEM, PBS vs CLOD. Dilation data is shown for the highest concentration of the dilator. SHRSP+CLOD had less perivascular MΦ around the cerebral arteries (0.7±0.1 vs 0.3±0.1, n=5, p<0.01). Pressurized MCAs from SHRSP+CLOD showed improved dilation to ADP (change from baseline: 32.8±3.4 vs 50.8±9.7μm, n=6, p<0.05). Endothelial function was further assessed with acetylcholine (Ach)±N‐nitro‐L‐arginine methyl ester (L‐NAME) by wire myography (n=7). MCAs from SHRSP+CLOD had improved dilation to Ach (%KCl constriction: 64.8±5.0 vs 51.8±4.4, p<0.05), which was blunted by L‐NAME (%KCl constriction: 80.8±7.6 vs 79.8±5.0). Endothelium‐independent dilation to sodium nitroprusside was unchanged (%KCl constriction: 39.4±3.2 vs 43.1±2.1). These data suggest that perivascular MΦ might reduce endothelial nitric oxide generation in MCAs from SHRSP.

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