Intensive physical training reduces intermittent hypoxia‐related vascular dysfunction by affecting the mechanisms of smooth muscle from molecular to physiological scales

Many excitable cells express L-type Ca2+ channels (LTCCs), which participate in physiological and pathophysiological processes ranging from memory, secretion, and contraction to epilepsy, heart failure, and hypertension. Clusters of LTCCs can operate in a PKCα-dependent, high open probability mode that generates sites of sustained Ca2+ influx called “persistent Ca2+ sparklets.” Although increased LTCC activity is necessary for the development of vascular dysfunction during hypertension, the mechanisms leading to increased LTCC function are unclear. Here, we tested the hypothesis that increased PKCα and persistent Ca2+ sparklet activity contributes to arterial dysfunction during hypertension. We found that PKCα and persistent Ca2+ sparklet activity is indeed increased in arterial myocytes during hypertension. Furthermore, in human arterial myocytes, PKCα-dependent persistent Ca2+ sparklets activated the prohypertensive calcineurin/NFATc3 signaling cascade. These events culminated in three hallmark signs of hypertension-associated vascular dysfunction: increased Ca2+ entry, elevated arterial [Ca2+]i, and enhanced myogenic tone. Consistent with these observations, we show that PKCα ablation is protective against the development of angiotensin II-induced hypertension. These data support a model in which persistent Ca2+ sparklets, PKCα, and calcineurin form a subcellular signaling triad controlling NFATc3-dependent gene expression, arterial function, and blood pressure. Because of the ubiquity of these proteins, this model may represent a general signaling pathway controlling gene expression and cellular function.

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Abstract 310: Deoxycorticosterone Acetate (doca)-salt Exacerbates Hypertension and Vascular Dysfunction in Mice Expressing Dominant Negative Peroxisome Proliferator-activated Receptor-gamma (pparg) in Smooth Muscle

Hypertension ◽

10.1161/hyp.62.suppl_1.a310 ◽

2013 ◽

Vol 62 (suppl_1) ◽

Author(s):

Pimonrat Ketsawatsomkron ◽

Deborah R Davis ◽

Aline M Hilzendeger ◽

Justin L Grobe ◽

Curt D Sigmund

Keyword(s):

Blood Pressure ◽

Smooth Muscle ◽

Transgenic Mice ◽

Vascular Function ◽

Vascular Dysfunction ◽

Critical Role ◽

Surrogate Marker ◽

Dominant Negative ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor

PPARG, a ligand-activated transcription factor plays a critical role in the regulation of blood pressure and vascular function. We hypothesized that smooth muscle cell (SMC) PPARG protects against hypertension (HT) and resistance vessel dysfunction. Transgenic mice expressing dominant negative PPARG (S-P467L) in SMC or non-transgenic controls (NT) were implanted with DOCA pellet and allowed ad libitum access to 0.15 M NaCl for 21 days in addition to regular chow and water. Blood pressure was monitored by telemetry and mesenteric arterial (MA) function was assessed by pressurized myograph. At baseline, 24-hour mean arterial pressure (MAP) was similar between NT and S-P467L mice, while the transgenic mice were tachycardic. DOCA-salt increased MAP to a much greater degree in S-P467L mice (Δ MAP; S-P467L: +34.2±6.0, NT: +13.3±5.7, p<0.05 vs NT). Heart rate was similarly decreased in both groups after DOCA-salt. Vasoconstriction to KCl, phenylephrine and endothelin-1 did not differ in MA from DOCA-salt treated NT and S-P467L, while the response to vasopressin was significantly reduced in S-P467L after DOCA-salt (% constriction at 10-8 M, S-P467L: 31.6±5.6, NT: 46.7±3.8, p<0.05 vs NT). Urinary copeptin, a surrogate marker for arginine vasopressin was similar in both groups regardless of treatment. Vasorelaxation to acetylcholine was slightly impaired in S-P467L MA compared to NT at baseline whereas this effect was further exaggerated after DOCA-salt (% relaxation at 10-5 M, S-P467L: 56.1±8.3, NT: 79.4±5.6, p<0.05 vs NT). Vascular morphology at luminal pressure of 75 mmHg showed a significant increase in wall thickness (S-P467L: 18.7±0.8, NT: 16.0±0.4, p<0.05 vs NT) and % media/lumen (S-P467L: 8.4±0.3, NT: 7.1±0.2, p<0.05 vs NT) in S-P467L MA after DOCA-salt. Expression of tissue inhibitor of metalloproteinases (TIMP)-4 and regulator of G-protein signaling (RGS)-5 transcript were 2- and 3.5-fold increased, respectively, in MA of NT with DOCA-salt compared to NT baseline. However, this induction was markedly blunted in S-P467L MA. We conclude that interference with PPARG function in SMC leads to altered gene expression crucial for normal vascular homeostasis, thereby sensitizing the mice to the effects of DOCA-salt induced HT and vascular dysfunction.

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Abstract P281: Vascular Remodeling And Impaired Vascular Smooth Muscle Cell Plasticity In Age And Sex-dependent Hypertension

Hypertension ◽

10.1161/hyp.78.suppl_1.p281 ◽

2021 ◽

Vol 78 (Suppl_1) ◽

Author(s):

Razie Amraei ◽

Kayla Nist ◽

Jesse Moreira ◽

Richard D Wainford

Keyword(s):

Smooth Muscle ◽

Vascular Smooth Muscle ◽

Smooth Muscle Cell ◽

Abdominal Aorta ◽

Vascular Remodeling ◽

Vascular Dysfunction ◽

Renal Arteries ◽

Cell Plasticity ◽

Sd Rats ◽

Age And Sex

Aim: Hypertension (HTN) and aging are associated with the development of vascular dysfunction. We speculated that vascular smooth muscle cell plasticity and vascular remodeling play major roles in age and sex-dependent HTN. Methods: Male and female Sprague-Dawley (SD) rats aged 3 and 16-months-old (N=6/group) were housed under standard conditions. Blood pressure was measured via femoral artery cannulation and sympathetic tone to the vasculature was estimated by ganglion blockade via Hexamethonium (30mg/Kg IV). PBS-perfused abdominal aorta and renal arteries were collected and immunoblotting was performed following protein extraction. Results: Male SD rats, but not females, develop HTN and increased sympathetic tone with age. Aged hypertensive male rats, but not aged normotensive females, exhibit reduced p-Erk1/2 and p-eNos levels in both abdominal aorta and renal arteries. α-Smooth Muscle Actin significantly increased in aged male abdominal aorta. Elevated c-Src was observed in aged female abdominal aorta and p-c-Src was reduced in aged male abdominal aorta. Caveolin-1 changed oppositely in young and aged abdominal aorta and renal arteries of two sexes. Conclusions: Our data suggest that artery-specific changes of key signaling molecules contribute to impaired vascular smooth muscle plasticity and vascular dysfunction in aged hypertensive male but not in aged normotensive female rats.

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Smooth Muscle Cell–Specific Disruption of the BBSome Causes Vascular Dysfunction

Hypertension ◽

10.1161/hypertensionaha.119.13382 ◽

2019 ◽

Vol 74 (4) ◽

pp. 817-825 ◽

Cited By ~ 4

Author(s):

John J. Reho ◽

Deng-Fu Guo ◽

Donald A. Morgan ◽

Kamal Rahmouni

Keyword(s):

Smooth Muscle ◽

Smooth Muscle Cell ◽

Muscle Cell ◽

Vascular Dysfunction

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Interleukin-9 Deletion Relieves Vascular Dysfunction and Decreases Blood Pressure via the STAT3 Pathway in Angiotensin II-Treated Mice

Mediators of Inflammation ◽

10.1155/2020/5741047 ◽

2020 ◽

Vol 2020 ◽

pp. 1-12 ◽

Cited By ~ 1

Author(s):

Yunzhao Yang ◽

Shaoqun Tang ◽

Chunchun Zhai ◽

Xin Zeng ◽

Qingjian Liu ◽

...

Keyword(s):

Blood Pressure ◽

Smooth Muscle ◽

Angiotensin Ii ◽

Inflammatory Response ◽

Vascular Dysfunction ◽

Control Group ◽

Dependent Manner ◽

Ang Ii ◽

Stat3 Pathway

Background. Multiple interleukin (IL) family members were reported to be closely related to hypertension. We aimed to investigate whether IL-9 affects angiotensin II- (Ang II-) induced hypertension in mice. Methods. Mice were treated with Ang II, and IL-9 expression was determined. In addition, effects of IL-9 knockout (KO) on blood pressure were observed in Ang II-infused mice. To determine whether the effects of IL-9 on blood pressure was mediated by the signal transducer and activator of the transcription 3 (STAT3) pathway, Ang II-treated mice were given S31-201. Furthermore, circulating IL-9 levels in patients with hypertension were measured. Results. Ang II treatment increased serum and aortic IL-9 expression in a dose-dependent manner; IL-9 levels were the highest in the second week and continued to remain high into the fourth week after the treatment. IL-9 KO downregulated proinflammatory cytokine expression, whereas it upregulated anti-inflammatory cytokine levels, relieved vascular dysfunction, and decreased blood pressure in Ang II-infused mice. IL-9 also reduced smooth muscle 22α (SM22α) expression and increased osteopontin (OPN) levels both in mice and in vitro. The effects of IL-9 KO on blood pressure and inflammatory response were significantly reduced by S31-201 treatment. Circulating IL-9 levels were significantly increased in patients with the hypertension group than in the control group, and elevated IL-9 levels positively correlated with both systolic blood pressure and diastolic blood pressure in patients with hypertension. Conclusions. IL-9 KO alleviates inflammatory response, prevents phenotypic transformation of smooth muscle, reduces vascular dysfunction, and lowers blood pressure via the STAT3 pathway in Ang II-infused mice. IL-9 might be a novel target for the treatment and prevention of clinical hypertension.

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Low-intensity interval exercise training attenuates coronary vascular dysfunction and preserves Ca2+-sensitive K+ current in miniature swine with LV hypertrophy

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00610.2011 ◽

2011 ◽

Vol 301 (4) ◽

pp. H1687-H1694 ◽

Cited By ~ 20

Author(s):

Craig A. Emter ◽

Darla L. Tharp ◽

Jan R. Ivey ◽

Venkataseshu K. Ganjam ◽

Douglas K. Bowles

Keyword(s):

Smooth Muscle ◽

Exercise Training ◽

Smooth Muscle Cell ◽

Vascular Function ◽

Vascular Dysfunction ◽

Miniature Swine ◽

Vascular Conductance ◽

Coronary Smooth Muscle ◽

Interval Exercise ◽

Low Intensity

Coronary vascular dysfunction has been observed in several models of heart failure (HF). Recent evidence indicates that exercise training is beneficial for patients with HF, but the precise intensity and underlying mechanisms are unknown. Left ventricular (LV) hypertrophy can play a significant role in the development of HF; therefore, the purpose of this study was to assess the effects of low-intensity interval exercise training on coronary vascular function in sedentary (HF) and exercise trained (HF-TR) aortic-banded miniature swine displaying LV hypertrophy. Six months postsurgery, in vivo coronary vascular responses to endothelin-1 (ET-1) and adenosine were measured in the left anterior descending coronary artery. Baseline and maximal coronary vascular conductance were similar between all groups. ET-1-induced reductions in coronary vascular conductance ( P < 0.05) were greater in HF vs. sedentary control and HF-TR groups. Pretreatment with the ET type A (ETA) receptor blocker BQ-123 prevented ET-1 hypersensitivity in HF animals. Whole cell voltage clamp was used to characterize composite K+ currents ( IK+) in coronary smooth muscle cells. Raising internal Ca2+ from 200 to 500 nM increased Ca2+-sensitive K+ current in HF-TR and control, but not HF animals. In conclusion, an ETA-receptor-mediated hypersensitivity to ET-1, elevated resting LV wall tension, and decreased coronary smooth muscle cell Ca2+-sensitive IK+ was found in sedentary animals with LV hypertrophy. Low-intensity interval exercise training preserved normal coronary vascular function and smooth muscle cell Ca2+-sensitive IK+, illustrating a potential mechanism underlying coronary vascular dysfunction in a large-animal model of LV hypertrophy. Our results demonstrate the potential clinical impact of exercise on coronary vascular function in HF patients displaying pathological LV hypertrophy.

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Impairment of IKCa channels contributes to uteroplacental endothelial dysfunction in rat diabetic pregnancy

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00901.2014 ◽

2015 ◽

Vol 309 (4) ◽

pp. H592-H604 ◽

Cited By ~ 10

Author(s):

Natalia I. Gokina ◽

Adrian D. Bonev ◽

Julie Phillips ◽

Alexander P. Gokin ◽

Kelsey Veilleux ◽

...

Keyword(s):

Smooth Muscle ◽

Membrane Potential ◽

Endothelial Dysfunction ◽

Smooth Muscle Cell ◽

Muscle Cell ◽

Vascular Dysfunction ◽

Citrate Buffer ◽

Pregnant Rats ◽

Intracellular Ca ◽

The Impact

Diabetes in rat pregnancy is associated with impaired vasodilation of the maternal uteroplacental vasculature. In the present study, we explored the role of endothelial cell (EC) Ca2+-activated K+ channels of small conductance (SKCa channels) and intermediate conductance (IKCa channels) in diabetes-induced uterine vascular dysfunction. Diabetes was induced by injection of streptozotocin to second-day pregnant rats and confirmed by the development of maternal hyperglycemia. Control rats were injected with citrate buffer. Changes in smooth muscle cell intracellular Ca2+ concentration, membrane potential, and vasodilation induced by SKCa/IKCa channel activators were studied in uteroplacental arteries of control and diabetic rats. The impact of diabetes on SKCa- and IKCa-mediated currents was explored in freshly dissociated ECs. NS309 evoked a potent vasodilation that was effectively inhibited by TRAM-34 but not by apamin. NS309-induced smooth muscle cell intracellular Ca2+ concentration, membrane potential, and dilator responses were significantly diminished by diabetes; N-cyclohexyl- N-2-(3,5-dimethyl-pyrazol-1-yl)-6-methyl-4-pyrimidinamine (CyPPA)-evoked responses were not affected. Ca2+-activated ion currents in ECs were insensitive to paxilline, markedly inhibited by charybdotoxin (ChTX), and diminished by apamin. NS309-induced EC currents were generated mostly due to activation of ChTX-sensitive channels. Maternal diabetes resulted in a significant reduction in ChTX-sensitive currents with no effect on apamin-sensitive or CyPPA-induced currents. We concluded that IKCa channels play a prevalent role over SKCa channels in the generation of endothelial K+ currents and vasodilation of uteroplacental arteries. Impaired function of IKCa channels importantly contributes to diabetes-induced uterine endothelial dysfunction. Therapeutic restoration of IKCa channel function may be a novel strategy for improvement of maternal uteroplacental blood flow in pregnancies complicated by diabetes.

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Soluble guanylyl cyclase is a target of angiotensin II-induced nitrosative stress in a hypertensive rat model

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00138.2012 ◽

2012 ◽

Vol 303 (5) ◽

pp. H597-H604 ◽

Cited By ~ 30

Author(s):

Pierre-Antoine Crassous ◽

Samba Couloubaly ◽

Can Huang ◽

Zongmin Zhou ◽

Padmamalini Baskaran ◽

...

Keyword(s):

Oxidative Stress ◽

Smooth Muscle ◽

Angiotensin Ii ◽

Guanylyl Cyclase ◽

Vascular Reactivity ◽

Nitrosative Stress ◽

Vascular Dysfunction ◽

Soluble Guanylyl Cyclase ◽

Smooth Muscle Relaxation ◽

Ang Ii

Nitric oxide (NO) by activating soluble guanylyl cyclase (sGC) is involved in vascular homeostasis via induction of smooth muscle relaxation. In cardiovascular diseases (CVDs), endothelial dysfunction with altered vascular reactivity is mostly attributed to decreased NO bioavailability via oxidative stress. However, in several studies, relaxation to NO is only partially restored by exogenous NO donors, suggesting sGC impairment. Conflicting results have been reported regarding the nature of this impairment, ranging from decreased expression of one or both subunits of sGC to heme oxidation. We showed that sGC activity is impaired by thiol S-nitrosation. Recently, angiotensin II (ANG II) chronic treatment, which induces hypertension, was shown to generate nitrosative stress in addition to oxidative stress. We hypothesized that S-nitrosation of sGC occurs in ANG II-induced hypertension, thereby leading to desensitization of sGC to NO hence vascular dysfunction. As expected, ANG II infusion increases blood pressure, aorta remodeling, and protein S-nitrosation. Intravital microscopy indicated that cremaster arterioles are resistant to NO-induced vasodilation in vivo in anesthetized ANG II-treated rats. Concomitantly, NO-induced cGMP production decreases, which correlated with S-nitrosation of sGC in hypertensive rats. This study suggests that S-nitrosation of sGC by ANG II contributes to vascular dysfunction. This was confirmed in vitro by using A7r5 smooth muscle cells infected with adenoviruses expressing sGC or cysteine mutants: ANG II decreases NO-stimulated activity in the wild-type but not in one mutant, C516A. This result indicates that cysteine 516 of sGC mediates ANG II-induced desensitization to NO in cells.

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Neural programming of mesenteric and renal arteries

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00250.2014 ◽

2014 ◽

Vol 307 (4) ◽

pp. H563-H573 ◽

Cited By ~ 13

Author(s):

John J. Reho ◽

Xiaoxu Zheng ◽

James E. Benjamin ◽

Steven A. Fisher

Keyword(s):

Smooth Muscle ◽

Ex Vivo ◽

Vascular Dysfunction ◽

Force Production ◽

Genetically Engineered ◽

Mesenteric Arteries ◽

Regulatory Subunit ◽

Mesenteric Circulation ◽

Genetically Engineered Mice

There is evidence for developmental origins of vascular dysfunction yet little understanding of maturation of vascular smooth muscle (VSM) of regional circulations. We measured maturational changes in expression of myosin phosphatase (MP) and the broader VSM gene program in relation to mesenteric small resistance artery (SRA) function. We then tested the role of the sympathetic nervous system (SNS) in programming of SRAs and used genetically engineered mice to define the role of MP isoforms in the functional maturation of the mesenteric circulation. Maturation of rat mesenteric SRAs as measured by qPCR and immunoblotting begins after the second postnatal week and is not complete until maturity. It is characterized by induction of markers of VSM differentiation (smMHC, γ-, α-actin), CPI-17, an inhibitory subunit of MP and a key target of α-adrenergic vasoconstriction, α1-adrenergic, purinergic X1, and neuropeptide Y1 receptors of sympathetic signaling. Functional correlates include maturational increases in α-adrenergic-mediated force and calcium sensitization of force production (MP inhibition) measured in first-order mesenteric arteries ex vivo. The MP regulatory subunit Mypt1 E24+/LZ- isoform is specifically upregulated in SRAs during maturation. Conditional deletion of mouse Mypt1 E24 demonstrates that splicing of E24 causes the maturational reduction in sensitivity to cGMP-mediated vasorelaxation (MP activation). Neonatal chemical sympathectomy (6-hydroxydopamine) suppresses maturation of SRAs with minimal effect on a conduit artery. Mechanical denervation of the mature rat renal artery causes a reversion to the immature gene program. We conclude that the SNS captures control of the mesenteric circulation by programming maturation of the SRA smooth muscle.

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