Impaired pressure-induced constriction in mouse middle cerebral arteries of ASIC2 knockout mice

2008 ◽  
Vol 294 (4) ◽  
pp. H1793-H1803 ◽  
Author(s):  
Kimberly P. Gannon ◽  
Lauren G. VanLandingham ◽  
Nikki L. Jernigan ◽  
Samira C. Grifoni ◽  
Gina Hamilton ◽  
...  
Keyword(s):  
Ion Channel ◽  
Sensory Neurons ◽  
Knockout Mice ◽  
Cerebral Arteries ◽  
Normal Pressure ◽  
Intraluminal Pressure ◽  
Myogenic Tone ◽  
Wild Type ◽  
Middle Cerebral Arteries

Recent studies from our laboratory demonstrated the importance of mechanosensitive epithelial Na+ channel (ENaC) proteins in pressure-induced constriction in renal and cerebral arteries. ENaC proteins are closely related to acid-sensing ion channel 2 (ASIC2), a protein known to be required for normal mechanotransduction in certain sensory neurons. However, the role of the ASIC2 protein in pressure-induced constriction has never been addressed. The goal of the current study was to investigate the role of ASIC2 proteins in pressure-induced, or myogenic, constriction in the mouse middle cerebral arteries (MCAs) from ASIC2 wild-type (+/+), heterozygous (+/−), and null (−/−) mice. Constrictor responses to KCl (20–80 mM) and phenylephrine (10−7–10−4 M) were not different among groups. However, vasoconstrictor responses to increases in intraluminal pressure (15–90 mmHg) were impaired in MCAs from ASIC2−/− and +/− mice. At 60 and 90 mmHg, MCAs from ASIC2+/+ mice generated 13.7 ± 2.1% and 15.8 ± 2.0% tone and ASIC2−/− mice generated 7.4 ± 2.8% and 12.5 ± 2.4% tone, respectively. Surprisingly, MCAs from ASIC2+/− mice generated 1.2 ± 2.2% and 3.9 ± 1.8% tone at 60 and 90 mmHg. The reason underlying the total loss of myogenic tone in the ASIC2+/− is not clear, although the loss of mechanosensitive β- and γ-ENaC proteins may be a contributing factor. These results demonstrate that normal ASIC2 expression is required for normal pressure-induced constriction in the MCA. Furthermore, ASIC2 may be involved in establishing the basal level of myogenic tone.

scholarly journals Increased pressure-induced tone in rat parenchymal arterioles vs. middle cerebral arteries: role of ion channels and calcium sensitivity

2014 ◽  
Vol 117 (1) ◽  
pp. 53-59 ◽  
Author(s):  
Marilyn J. Cipolla ◽  
Julie Sweet ◽  
Siu-Lung Chan ◽  
Matthew J. Tavares ◽  
Natalia Gokina ◽  
...  
Keyword(s):  
Ion Channel ◽  
Small Vessel Disease ◽  
Cerebral Arteries ◽  
Calcium Sensitivity ◽  
Cytosolic Calcium ◽  
Intraluminal Pressure ◽  
Myogenic Tone ◽  
Contractile Apparatus ◽  
Pial Arteries ◽  
Middle Cerebral Arteries

Brain parenchymal arterioles (PAs) are high-resistance vessels that branch off pial arteries and perfuse the brain parenchyma. PAs are the target of cerebral small vessel disease and have been shown to have greater pressure-induced tone at lower pressures than pial arteries. We investigated mechanisms by which brain PAs have increased myogenic tone compared with middle cerebral arteries (MCAs), focusing on differences in vascular smooth muscle (VSM) calcium and ion channel function. The amount of myogenic tone and VSM calcium was measured using Fura 2 in isolated and pressurized PAs and MCAs. Increases in intraluminal pressure caused larger increases in tone and cytosolic calcium in PAs compared with MCAs. At 50 mmHg, myogenic tone was 37 ± 5% for PAs vs. 6.5 ± 4% for MCAs ( P < 0.01), and VSM calcium was 200 ± 20 nmol/l in PAs vs. 104 ± 15 nmol/l in MCAs ( P < 0.01). In vessels permeabilized with Staphylococcus aureus α-toxin, PAs were not more sensitive to calcium, suggesting calcium sensitization was not at the level of the contractile apparatus. PAs were 30-fold more sensitive to the voltage-dependent calcium channel (VDCC) inhibitor nifedipine than MCAs (EC50 for PAs was 3.5 ± 0.4 vs. 82.1 ± 2.1 nmol/l for MCAs; P < 0.01); however, electrophysiological properties of the VDCC were not different in VSM. PAs had little to no response to the calcium-activated potassium channel inhibitor iberiotoxin, whereas MCAs constricted ∼15%. Thus increased myogenic tone in PAs appears related to differences in ion channel activity that promotes VSM membrane depolarization but not to a direct sensitization of the contractile apparatus to calcium.

scholarly journals Intracellular Acidification Alters Myogenic Responsiveness and Vasomotion of Mouse Middle Cerebral Arteries

2013 ◽  
Vol 34 (1) ◽  
pp. 161-168 ◽  
Author(s):  
Axel BK Thomsen ◽  
Sukhan Kim ◽  
Filip Aalbaek ◽  
Christian Aalkjaer ◽  
Ebbe Boedtkjer
Keyword(s):  
Knockout Mice ◽  
Kinase Inhibitor ◽  
Cerebral Arteries ◽  
Rho Kinase ◽  
Vascular Wall ◽  
Mesenteric Arteries ◽  
Myogenic Tone ◽  
No Production ◽  
Wild Type ◽  
Middle Cerebral Arteries

Intracellular pH (pHi) in the vascular wall modulates agonist-induced vasocontractile and vasorelaxant responses in mesenteric arteries, whereas effects on myogenic tone have been unsettled. We studied the role of Na+,HCO3− cotransporter NBCn1 in mouse isolated middle cerebral arteries and the influence of pHi disturbances on myogenic tone. Na+,HCO3− cotransport was abolished in arteries from NBCn1 knockout mice and steady-state pHi ∼0.3 units reduced compared with wild-type mice. Myogenic tone development was low under control conditions but increased on treatment with the NO-synthase inhibitor N-nitro-L-arginine methyl ester (L-NAME). This effect of L-NAME was smaller in arteries from NBCn1 knockout than wild-type mice. Myogenic tone with L-NAME present was significantly lower in arteries from NBCn1 knockout than wild-type mice and was abolished by rho-kinase inhibitor Y-27632. The arteries displayed vasomotion, and this rhythmic contractile pattern was also attenuated in arteries from NBCn1 knockout mice. No differences in membrane potential or intracellular [Ca2+] were seen between arteries from NBCn1 knockout and wild-type mice. We propose that NO production and rho-kinase-dependent Ca2+ sensitivity are reduced at low pHi in pressurized mouse middle cerebral arteries. This likely impedes the ability to adjust to changes in perfusion pressure and regulate cerebral blood flow.

Evidence for a functional calcium-sensing receptor that modulates myogenic tone in rat subcutaneous small arteries

2005 ◽  
Vol 288 (4) ◽  
pp. H1756-H1762 ◽  
Author(s):  
Jacqueline Ohanian ◽  
Kelly M. Gatfield ◽  
Donald T. Ward ◽  
Vasken Ohanian
Keyword(s):  
Vascular Tissue ◽  
Immunoblot Analysis ◽  
Negative Regulator ◽  
Intraluminal Pressure ◽  
Myogenic Tone ◽  
Internal Diameter ◽  
Calcium Sensing Receptor ◽  
Small Arteries ◽  
Calcium Sensing

Myogenic tone of small arteries is dependent on the presence of extracellular calcium ([Formula: see text]), and, recently, a receptor that senses changes in Ca2+, the calcium-sensing receptor (CaR), has been detected in vascular tissue. We investigated whether the CaR is involved in the regulation of myogenic tone in rat subcutaneous small arteries. Immunoblot analysis using a monoclonal antibody against the CaR demonstrated its presence in rat subcutaneous arteries. To determine whether the CaR was functionally active, segments of artery (<250 μm internal diameter) mounted in a pressure myograph with an intraluminal pressure of 70 mmHg were studied after the development of myogenic tone. Increasing [Formula: see text] concentration ([Ca2+]o) cumulatively from 0.5 to 10 mM induced an initial constriction (0.5–2 mM) followed by dilation (42 ± 5% loss of tone). The dose-dependent dilation was mimicked by other known CaR agonists including magnesium (1–10 mM) and the aminoglycosides neomycin (0.003–10 mM) and kanamycin (0.003–3 mM). PKC activation with the phorbol ester phorbol-12,13-dibutyrate (20nM) inhibited the dilation induced by high [Ca2+]o or neomycin, whereas inhibition of PKC with GF109203X (10 μM) increased the responses to [Formula: see text] or neomycin, consistent with the role of PKC as a negative regulator of the CaR. We conclude that rat subcutaneous arteries express a functionally active CaR that may be involved in the modulation of myogenic tone and hence the regulation of peripheral vascular resistance.

scholarly journals NO can suppress myogenic tone in rat middle cerebral arteries by activating BK Ca

2006 ◽  
Vol 20 (5) ◽  
Author(s):  
Alister James McNeish ◽  
Kim Dora ◽  
Chris Garland
Keyword(s):  
Cerebral Arteries ◽  
Myogenic Tone ◽  
Middle Cerebral Arteries

scholarly journals Regulation of the cognitive aging process by the transcriptional repressor RP58

2021 ◽  
Author(s):  
Tomoko Tanaka ◽  
Shinobu Hirai ◽  
Hiroyuki Manabe ◽  
Kentaro Endo ◽  
Hiroko Shimbo ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Knockout Mice ◽  
Cognitive Aging ◽  
Critical Role ◽  
Harmful Effect ◽  
Transcriptional Repressor ◽  
Repair Pathway ◽  
Wild Type

Aging involves a decline in physiology which is a natural event in all living organisms. An accumulation of DNA damage contributes to the progression of aging. DNA is continually damaged by exogenous sources and endogenous sources. If the DNA repair pathway operates normally, DNA damage is not life threatening. However, impairments of the DNA repair pathway may result in an accumulation of DNA damage, which has a harmful effect on health and causes an onset of pathology. RP58, a zinc-finger transcriptional repressor, plays a critical role in cerebral cortex formation. Recently, it has been reported that the expression level of RP58 decreases in the aged human cortex. Furthermore, the role of RP58 in DNA damage is inferred by the involvement of DNMT3, which acts as a co-repressor for RP58, in DNA damage. Therefore, RP58 may play a crucial role in the DNA damage associated with aging. In the present study, we investigated the role of RP58 in aging. We used RP58 hetero-knockout and wild-type mice in adolescence, adulthood, or old age. We performed immunohistochemistry to determine whether microglia and DNA damage markers responded to the decline in RP58 levels. Furthermore, we performed an object location test to measure cognitive function, which decline with age. We found that the wild-type mice showed an increase in single-stranded DNA and gamma-H2AX foci. These results indicate an increase in DNA damage or dysfunction of DNA repair mechanisms in the hippocampus as age-related changes. Furthermore, we found that, with advancing age, both the wild-type and hetero-knockout mice showed an impairment of spatial memory for the object and increase in reactive microglia in the hippocampus. However, the RP58 hetero-knockout mice showed these symptoms earlier than the wild-type mice did. These results suggest that a decline in RP58 level may lead to the progression of aging.

scholarly journals Similarities and differences between IL11 and IL11RA1 knockout mice for lung fibro-inflammation, fertility and craniosynostosis

2020 ◽  
Author(s):  
Benjamin Ng ◽  
Anissa A. Widjaja ◽  
Sivakumar Viswanathan ◽  
Jinrui Dong ◽  
Sonia P. Chothani ◽  
...  
Keyword(s):  
Knockout Mice ◽  
Lung Fibroblasts ◽  
Loss Of Function ◽  
Wild Type ◽  
Reduced Body ◽  
Body Weights ◽  
Show Evidence ◽  
Similarities And Differences ◽  
The Impact

AbstractGenetic loss of function (LOF) in IL11RA infers IL11 signaling as important for fertility, fibrosis, inflammation and craniosynostosis. The impact of genetic LOF in IL11 has not been characterized. We generated IL11-knockout (Il11-/-) mice, which are born in normal Mendelian ratios, have normal hematological profiles and are protected from bleomycin-induced lung fibro-inflammation. Noticeably, baseline IL6 levels in the lungs of Il11-/- mice are lower than those of wild-type mice and are not induced by bleomycin damage, placing IL11 upstream of IL6. Lung fibroblasts from Il11-/- mice are resistant to pro-fibrotic stimulation and show evidence of reduced autocrine IL11 activity. Il11-/- female mice are infertile. Unlike Il11ra1-/- mice, Il11-/- mice do not have a craniosynostosis-like phenotype and exhibit mildly reduced body weights. These data highlight similarities and differences between LOF in IL11 or IL11RA while establishing further the role of IL11 signaling in fibrosis and stromal inflammation.

Sex-specific differences in cerebral arterial myogenic tone in hypertensive and normotensive rats

2006 ◽  
Vol 290 (3) ◽  
pp. H1081-H1089 ◽  
Author(s):  
Jamila Ibrahim ◽  
Ann McGee ◽  
Delyth Graham ◽  
John C. McGrath ◽  
Anna F. Dominiczak
Keyword(s):  
Blood Flow ◽  
Cerebral Arteries ◽  
Systemic Blood Pressure ◽  
Limiting Factors ◽  
Myogenic Tone ◽  
Spontaneously Hypertensive ◽  
Cerebrovascular Events ◽  
Middle Cerebral Arteries ◽  
Wistar Kyoto ◽  
Strain Dependent

Cerebral blood flow (CBF) is maintained constant despite changes in systemic blood pressure (BP) through multiple mechanisms of autoregulation such as vascular myogenic reactivity. Our aim was to determine myogenic characteristics of cannulated middle cerebral arteries (MCA) in male and female stroke-prone spontaneously hypertensive rats (SHRSP) and Wistar-Kyoto rats (WKY) at 12 wk of age under pressurised no-flow conditions. MCA pressure-diameter relationships (20–200 mmHg) were constructed in active (with calcium) and passive (without calcium) conditions, and myogenic and mechanical properties were determined. Myogenic reactivity in WKY ( P < 0.05) and SHRSP ( P < 0.05) males was impaired compared with their female counterparts. Comparison of SHRSP with WKY in males revealed similar myogenic reactivity, but in females SHRSP exhibited augmented myogenic reactivity ( P < 0.05). In both sexes, myogenic tone yielded at lower pressure in SHRSP compared with WKY vessels (120–140 vs. 140–180 mmHg). Stress-strain relationships and elastic moduli in WKY rats showed that vessels were stiffer in females than in males. Conversely, in SHRSP, male vessels were stiffer than female vessels. Comparison of strains in males indicated that stiffness was increased in SHRSP compared with WKY vessels, whereas the converse was observed in females. These findings demonstrate that MCA myogenic and distensibility characteristics exhibit significant sex- and strain-dependent differences. Inappropriate myogenic adaptation and augmented vascular stiffness, particularly in male SHRSP, are potential limiting factors in blood flow autoregulation and may increase the predisposition for stroke-related cerebrovascular events.

Functional heterogeneity of endothelial P2 purinoceptors in the cerebrovascular tree of the rat

1999 ◽  
Vol 277 (3) ◽  
pp. H893-H900 ◽  
Author(s):  
Junping You ◽  
T. David Johnson ◽  
Sean P. Marrelli ◽  
Robert M. Bryan
Keyword(s):  
Cerebral Arteries ◽  
No Synthase ◽  
Third Order ◽  
Selective Agonist ◽  
Middle Cerebral Arteries ◽  
Spontaneous Tone ◽  
A Minor ◽  
Calcium Activated Potassium Channel ◽  
Dose Dependent

The effects of stimulating P2Y1 or P2Y2 purinoceptors on the endothelium of isolated middle cerebral arteries (MCAs), third-order branches of the MCA (bMCAs), and penetrating arterioles (PAs) of the rat were studied. After pressurization and development of spontaneous tone (25% contraction), resting diameters for MCAs, bMCAs, and PAs were 203 ± 5 ( n = 50), 99 ± 2 ( n = 42), and 87 ± 2 μm ( n = 53), respectively. Luminal application of the P2Y1-selective agonist 2-methylthioadenosine 5′-triphosphate elicited dose-dependent dilations (or loss of intrinsic tone) in MCAs but not in bMCAs or PAs. The dilation in MCAs was completely blocked by removal of the endothelium or by nitro-l-arginine methyl ester (10−5 M), an inhibitor of NO synthase. Luminal application of the P2Y2-selective agonist ATP elicited dilations in MCAs, bMCAs, and PAs. Removal of the endothelium abolished the dilations in all vessel groups. Dilations in MCAs have been shown to involve both NO and endothelium-derived hyperpolarizing factor (EDHF). The dilations in bMCAs and PAs had a minor NO component and prominent EDHF component; that is, 1) the dilations to ATP were not diminished by the combined inhibition of NO synthase and cyclooxygenase, 2) the dilations were accompanied by significant hyperpolarizations of the vascular smooth muscle (∼15 mV), and 3) the dilations were completely abolished by the calcium-activated potassium channel blocker charybdotoxin. We concluded that the role of NO in purinoceptor-induced dilations diminishes along the cerebrovascular tree in the rat, whereas the role of EDHF becomes more prominent.

scholarly journals Disruption of CXCR6 Ameliorates Kidney Inflammation and Fibrosis in Deoxycorticosterone Acetate/Salt Hypertension

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Yuanbo Wu ◽  
Changlong An ◽  
Xiaogao Jin ◽  
Zhaoyong Hu ◽  
Yanlin Wang
Keyword(s):  
Knockout Mice ◽  
Critical Role ◽  
Kidney Injury ◽  
Wild Type ◽  
Salt Treatment ◽  
Hypertensive Nephropathy ◽  
Deoxycorticosterone Acetate ◽  
Kidney Fibrosis ◽  
Salt Hypertension

AbstractCirculating cells have a pathogenic role in the development of hypertensive nephropathy. However, how these cells infiltrate into the kidney are not fully elucidated. In this study, we investigated the role of CXCR6 in deoxycorticosterone acetate (DOCA)/salt-induced inflammation and fibrosis of the kidney. Following uninephrectomy, wild-type and CXCR6 knockout mice were treated with DOCA/salt for 3 weeks. Blood pressure was similar between wild-type and CXCR6 knockout mice at baseline and after treatment with DOCA/salt. Wild-type mice develop significant kidney injury, proteinuria, and kidney fibrosis after three weeks of DOCA/salt treatment. CXCR6 deficiency ameliorated kidney injury, proteinuria, and kidney fibrosis following treatment with DOCA/salt. Moreover, CXCR6 deficiency inhibited accumulation of bone marrow–derived fibroblasts and myofibroblasts in the kidney following treatment with DOCA/salt. Furthermore, CXCR6 deficiency markedly reduced the number of macrophages and T cells in the kidney after DOCA/salt treatment. In summary, our results identify a critical role of CXCR6 in the development of inflammation and fibrosis of the kidney in salt-sensitive hypertension.

Testosterone suppresses endothelium-dependent dilation of rat middle cerebral arteries

2004 ◽  
Vol 286 (2) ◽  
pp. H552-H560 ◽  
Author(s):  
Rayna J. Gonzales ◽  
Diana N. Krause ◽  
Sue P. Duckles
Keyword(s):  
Vascular Tone ◽  
Cerebral Arteries ◽  
Cerebrovascular Reactivity ◽  
Male Rats ◽  
Intraluminal Pressure ◽  
Vascular Effects ◽  
Additional Increase ◽  
Testosterone Treatment ◽  
Cox Inhibitor ◽  
Middle Cerebral Arteries

Little is known about vascular effects of testosterone. We previously reported chronic testosterone treatment increases vascular tone in middle cerebral arteries (MCA; 300 μm diameter) of male rats. In the present study, we investigated the hypothesis that physiological levels of circulating testosterone affect endothelial factors that modulate cerebrovascular reactivity. Small branches of MCA (150 μm diameter) were isolated from orchiectomized (ORX) and testosterone-treated (ORX+T) rats. Intraluminal diameters were recorded after step changes in intraluminal pressure (20–100 Torr) in the absence or presence of NG-nitro-l-arginine-methyl ester (l-NAME), a nitric oxide synthase (NOS) inhibitor; indomethacin, a cyclooxygenase (COX) inhibitor; and/or apamin and charybdotoxin (CTX); and KCa channel blockers used to inhibit endothelium-derived hyperpolarizing factors (EDHF). At intraluminal pressures ≥60 Torr, arteries from ORX+T developed greater tone compared with ORX arteries. This difference was abolished by removal of the endothelium but remained after treatment of intact arteries with indomethacin or l-NAME. In addition, testosterone treatment had no effect on cerebrovascular production of endothelin-1 or prostacyclin nor did it alter protein levels of endothelial NOS or COX-1. Endothelium removal after l-NAME/indomethacin exposure caused an additional increase in tone. Interestingly, the latter effect was smaller in arteries from ORX+T, suggesting testosterone affects endothelial vasodilators that are independent of NOS and COX. Apamin/CTX, in the presence of l-NAME/indomethacin, abolished the difference in tone between ORX and ORX+T and resulted in vessel diameters similar to those of endothelium-denuded preparations. In conclusion, testosterone may modulate vascular tone in cerebral arteries by suppressing EDHF.

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