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Proper brain function depends on neurovascular coupling: neural activity rapidly increases local blood flow to meet moment-to-moment changes in regional brain energy demand1. Neurovascular coupling is the basis for functional brain imaging2, and impaired neurovascular coupling is implicated in neurodegeneration1. The underlying molecular and cellular mechanisms of neurovascular coupling remain poorly understood. The conventional view is that neurons or astrocytes release vasodilatory factors that act directly on smooth muscle cells (SMCs) to induce arterial dilation and increase local blood flow1. Here, using two-photon microscopy to image neural activity and vascular dynamics simultaneously in the barrel cortex of awake mice under whisker stimulation, we found that arteriolar endothelial cells (aECs) have an active role in mediating neurovascular coupling. We found that aECs, unlike other vascular segments of endothelial cells in the central nervous system, have abundant caveolae. Acute genetic perturbations that eliminated caveolae in aECs, but not in neighbouring SMCs, impaired neurovascular coupling. Notably, caveolae function in aECs is independent of the endothelial NO synthase (eNOS)-mediated NO pathway. Ablation of both caveolae and eNOS completely abolished neurovascular coupling, whereas the single mutants exhibited partial impairment, revealing that the caveolae-mediated pathway in aECs is a major contributor to neurovascular coupling. Our findings indicate that vasodilation is largely mediated by endothelial cells that actively relay signals from the central nervous system to SMCs via a caveolae-dependent pathway.
1. Using conventional microelectrode techniques, membrane potentials were recorded from smooth muscle cells of guinea-pig choroidal arterioles. 2. Transmural stimulation initiated excitatory junction potentials (EJPs) which were abolished by either guanethidine or alpha,beta-methylene-ATP but not by phentolamine, indicating that they resulted from activation of purinoceptors. 3. Trains of stimuli evoked EJPs which were followed by a slow depolarization, an inhibitory junction potential (IJP) or a biphasic membrane potential change which consisted of an IJP and a subsequent slow depolarization. 4. Slow depolarizations were abolished by either phentolamine or guanethidine, indicating that they resulted from activation of alpha-adrenoceptors. 5. IJPs were abolished by atropine but not by guanethidine, and were reduced by 50 % by apamin with the residual response being abolished by charybdotoxin, indicating that they resulted from the activation of muscarinic receptors which open two sets of Ca2+-activated K+ channels. 6. Most responses were followed by slow hyperpolarizations. These were almost abolished by L-nitroarginine, an effect which was partly overcome by L-arginine, and were abolished by glibenclamide, indicating that they resulted from the release of NO and activation of ATP-sensitive K+ channels. 7. Immunohistochemical analysis showed that arterioles were densely innervated by adrenergic nerve fibres. A population of fibres, likely to be cholinergic, was also identified. Furthermore, populations of nerve fibres immunoreactive to antibodies against either nitric oxide synthase (NOS) or substance P (SP) were also identified. 8. These findings indicate that choroidal arterioles of the guinea-pig are innervated by at least three different populations of nerves, adrenergic nerves which evoke excitatory responses, cholinergic nerves which evoke inhibitory responses and a population of nerves which cause the release of NO.
Transient receptor potential vanilloid type 1 (TRPV1) is a major nociceptive ion channel implicated in bladder physiology and/or pathophysiology. However, the precise expression of TRPV1 in neuronal vs. nonneuronal bladder cells is uncertain. Here we used reporter mouse lines (TRPV1-Cre:tdTomato and TRPV1PLAP-nlacZ) to map expression of TRPV1 in postnatal bladder. TRPV1 was not detected in the urothelium, however, we found marked expression of TRPV1 lineage in sensory nerves, and surprisingly, in arterial/arteriolar smooth muscle (ASM) cells. Tomato fluorescence was prominent in the vesical arteries and in small-diameter (15-40 μm) arterioles located in the suburothelial layer with a near equal distribution in bladder dome and base. Notably, arteriolar TRPV1 expression was greater in females than in males and increased in both sexes after 90 days of age, suggesting sex hormone and age dependency. Analysis of whole bladder and vesical artery TRPV1 mRNA revealed a similar sex and developmental dependence. Pharmacological experiments confirmed functional TRPV1 protein expression; capsaicin increased intracellular Ca2+ in ∼15% of ASM cells from wild-type female bladders, but we observed no responses to capsaicin in bladder arterioles isolated from TRPV1-null mice. Furthermore, capsaicin triggered arteriole constriction that was rapidly reversed by the TRPV1 antagonist, BCTC. These data show that predominantly in postpubertal female mice, bladder ASM cells express functional TRPV1 channels that may act to constrict arterioles. TRPV1 may therefore play an important role in regulating the microcirculation of the female bladder, and this effect may be of significance during inflammatory conditions.
Ca(2+) imaging reveals subcellular Ca(2+) sparks and global Ca(2+) waves/oscillations in vascular smooth muscle. It is well established that Ca(2+) sparks can relax arteries, but we have previously reported that sparks can summate to generate Ca(2+) waves/oscillations in unpressurized retinal arterioles, leading to constriction. We have extended these studies to test the functional significance of Ca(2+) sparks in the generation of myogenic tone in pressurized arterioles.
1. We investigated by intravital microscopy in rats, the in vivo direct effects of theophylline on the diameters of second and third order diaphragm arterioles. 2. Theophylline (1-100 microM) dilated second and third order diaphragm arterioles significantly, and with an amplitude which was not statistically different from the one obtained with adenosine (1-100 microM). Enprofylline (1-100 microM), a theophylline analogue with poor adenosine-receptor antagonism but with similar or higher phosphodiesterases inhibition properties than theophylline, also dilated diaphragm arterioles, causing however, a significantly smaller dilatation than theophylline. 3. Neither the A1 adenosine receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (CPX, 50 nM), nor the A2 adenosine receptor antagonist 3,7-dimethyl-1-proparglyxanthine (DMPX, 10 microM) reduced significantly theophylline-induced arteriolar dilatation. 4. Theophylline (100 nM) abolished adenosine-induced arteriolar dilatation. 5. The dilatation induced by theophylline was unchanged by the nitric oxide (NO) synthase inhibitor N(omega)-nitro-L-arginine (NNA, 300 microM). 6. Theophylline-induced arteriolar dilatation was abolished by the prostaglandin synthesis inhibitors mefenamic acid or indomethacin (20 microM). 7. These findings show that theophylline induced a significant dilatation of diaphragm arterioles via the release of prostaglandins.
We studied the effects of a selective vasopressin V(1A) receptor antagonist [1-(1-(4-(3-acetylaminopropoxy)benzoyl)-4-piperidyl)-3, 4-dihydro-2(1H)-quinolinone (OPC-21268)] and a selective vasopressin V(2) receptor antagonist [5-dimethylamino-1(4-(2-methylbenzoylamino)benzoyl)-2,3,4, 5-tetrahydro-1H-benzazepine (OPC-31260)] on vasopressin-induced contraction of mesenteric and cremasteric arterioles in urethane-anaesthetized rats. Vasopressin was infused intravenously for 60 min or applied topically to arterioles directly. Vasopressin infusion (50, 100 or 500 ng/kg/min) decreased the diameter of both mesenteric and cremasteric arterioles. Vasopressin (500 ng/kg/min)-induced vasoconstriction was antagonized by OPC-21268 (0. 2, 1.0 and 5.0 mg/kg, i.v.), dose-dependently, but not by OPC-31260. Topically applied vasopressin (4.6x10(-10)-4.6x10(-8) M) dose-dependently constricted both microvessels. Pre-administration of OPC-21268 (5.0 mg/kg, i.v.) completely inhibited topically applied vasopressin-induced vasoconstriction in both microvessels, and OPC-31260 partially inhibited it in cremasteric arterioles. These results suggest that vasopressin induces vasoconstriction in rat mesenteric and cremasteric arterioles mainly by stimulating vasopressin V(1A) receptors, while vasoconstriction in cremasteric arterioles is partly associated with stimulation of vasopressin V(2) receptors.
Glaucoma is a leading cause of severe visual impairment and blindness. Although high intraocular pressure (IOP) is an established risk factor for the disease, the role of abnormal ocular vessel function in the pathophysiology of glaucoma gains more and more attention. We tested the hypothesis that elevated intraocular pressure (IOP) causes vascular dysfunction in the retina.
During exercise in humans, circulating levels of ATP and K+ increase at a time when blood flow increases to satisfy metabolic demand. Both molecules can activate arteriolar K+ channels to stimulate vasodilatation; here, it is established whether conducted dilatation is observed in a skeletal muscle bed.
The olfactory receptor Olfr78 (prostate-specific G protein-coupled receptor PSGR) is a member of the G protein-coupled receptor family mediating olfactory chemosensation, but it is additionally expressed in other tissues. Olfr78 expressed in kidney participates in blood pressure regulation, and in prostate it plays a role in the development of cancer. We here screened many organs/tissues of transgenic mice co-expressing β-galactosidase with Olfr78. X-gal-positive cells were detectable in smooth muscle cells of numerous arterioles of striated muscles (heart ventricles and skeletal muscles of various embryological origin). In addition, in most organs where we found expression of Olfr78 mRNA, X-gal staining was restricted to smooth muscle cells of small blood vessels. The dominant expression of Olfr78 in arteriolar smooth muscle cells supports the concept of an important role in blood pressure regulation and suggests a participation in the fine tuning of blood supply especially of striated muscles. This should be considered when targeting Olfr78 in other contexts such as prostate cancer.
Despite data showing that estrogen is vasculoprotective in large conduit arteries, hormone therapy (HT) during menopause has not proven to mitigate cardiovascular disease (CVD) risk. Estrogen exposure through prolonged oral contraceptive use and gender-affirming therapy can also increase cis- and trans-females' risk for future CVD, respectively. The microvasculature is a unique vascular bed that when dysfunctional can independently predict future adverse cardiac events; however, studies on the influence of estrogen on human microvessels are limited. Here, we show that isolated human arterioles from females across the life span maintain nitric oxide (NO)-mediated dilation to flow, whereas chronic (16-20 h) exposure to exogenous (100 nM) 17β-estradiol promotes microvascular endothelial dysfunction in vessels from adult females of <40 and ≥40 yr of age. The damaging effect of estrogen was more dramatic in arterioles from biological males, as they exhibited both endothelial and smooth muscle dysfunction. Furthermore, females of <40 yr have greater endothelial expression of estrogen receptor-β (ER-β) and G protein-coupled estrogen receptor (GPER) compared with females of ≥40 yr and males. Estrogen receptor-α (ER-α), the prominent receptor associated with protective effects of estrogen, was identified within the adventitia as opposed to the endothelium across all groups. To our knowledge, this is the first study to report the detrimental effects of estrogen on the human microvasculature and highlights differences in estrogen receptor expression.NEW & NOTEWORTHY Microvascular dysfunction is an independent predictor of adverse cardiac events; however, the effect of estrogen on the human microcirculation represents a critical knowledge gap. To our knowledge, this is the first study to report sex-specific detrimental effects of chronic estrogen on human microvascular reactivity. These findings may offer insight into the increased CVD risk associated with estrogen use in both cis- and trans-females.
The cellular mechanisms underlying vasomotion of irideal arterioles from juvenile rats have been studied using electrophysiological methods, ratiometric calcium measurements and video microscopy. Vasomotion was not affected by removal of the endothelium. Spontaneous contractions were preceded by spontaneous depolarizations. Both were abolished by the intracellular calcium chelator, BAPTA AM (20 microM), but not by ryanodine (10 microM), suggesting a dependence on the cyclical release of calcium from intracellular stores, other than those operated by ryanodine receptors. Oscillations were little changed when the membrane potential of short segments of arteriole was either depolarized or hyperpolarized. When the segments were voltage clamped, oscillating inward currents were recorded, indicating that the changes in membrane potential were voltage independent. Vasomotion was preceded by intracellular calcium oscillations and both were abolished by inhibitors of phospholipase C (U73122, 10 microM), phospholipase A(2) (AACOCF(3), 30 microM) and protein kinase C (chelerythrine chloride, 5 microM, and myristoylated protein kinase C peptide, 10 microM). Inhibition of vasomotion by the dual lipoxygenase and cyclo-oxygenase inhibitor, NDGA (10 microM), the lipoxygenase inhibitor, ETI (1 microM) but not by the cyclo-oxygenase inhibitors, aspirin (10 microM) and indomethacin (10 microM), or the cytochrome P450 inhibitor 17-ODYA (10 microM), suggested an involvement of the lipoxygenase pathway. The observations suggest that vasomotion of iris arterioles is voltage independent and results from the cyclical release of calcium from IP(3)-sensitive stores which are activated by cross talk between the phospholipase C and phospholipase A(2) pathways in vascular smooth muscle.
Analysis of microvascular parameters in the retinal circulation-known to reflect those in the systemic circulation-allows us to differentiate between eutrophic and hypertrophic remodelling of small arteries. This study aimed to examine microvascular changes in patients with congestive heart failure (CHF) and reduced as well as mid-range ejection fraction.
1. Mechanisms underlying spontaneous rhythmical contractions have been studied in irideal arterioles of the rat using video microscopy and electrophysiology. 2. Rhythmical contractions (4 min-1) were more common during the second and third postnatal weeks and were always preceded by large, slow depolarizations (5-40 mV). 3. Spontaneous contractions were unaffected by tetrodotoxin (1 microM), neurotransmitter receptor antagonists, the sympathetic neurone blocker, guanethidine (5 microM) or sensory neurotoxin, capsaicin (1 microM). 4. Stimulation of sensory nerves inhibited spontaneous activity and this was not prevented by L-NAME (10 microm). 5. L-NAME (10 microm) caused an increase in frequency of spontaneous contractions, while forskolin (30 nM), in the presence of L-NAME, abolished spontaneous, but not nerve-mediated, contractions. 6. Spontaneous activity was not affected by felodipine (1 nM) or nifedipine (1 microM), but was abolished by cadmium chloride (1 microM) or superfusion with calcium-free solution. 7. Caffeine (1 mM), thapsigargin (2 microM) and cyclopiazonic acid (3 microM), but not ryanodine (3 microM), abolished spontaneous and nerve-mediated contractions. After preincubation in L-NAME (10 microM), cyclopiazonic acid abolished spontaneous contractions only. 8. Spontaneous depolarizations and contractions were abolished by 18alpha-glycyrrhetinic acid (20 microM). 9. Results suggest that spontaneous rhythmical contractions are myogenic and result from the cyclical release of calcium from intracellular stores, without a contribution from voltage-dependent calcium channels. Intercellular coupling through gap junctions appears to be essential for co-ordination of these events which could be modulated by nitric oxide and increases in cAMP. The possibility that different intracellular stores underly spontaneous and nerve-mediated contractions is discussed.
Active neurons increase their energy supply by dilating nearby arterioles and capillaries. This neurovascular coupling underlies blood oxygen level-dependent functional imaging signals, but its mechanism is controversial. Canonically, neurons release glutamate to activate metabotropic glutamate receptor 5 (mGluR5) on astrocytes, evoking Ca2+ release from internal stores, activating phospholipase A2 and generating vasodilatory arachidonic acid derivatives. However, adult astrocytes lack mGluR5, and knockout of the inositol 1,4,5-trisphosphate receptors that release Ca2+ from stores does not affect neurovascular coupling. We now show that buffering astrocyte Ca2+ inhibits neuronally evoked capillary dilation, that astrocyte [Ca2+]i is raised not by release from stores but by entry through ATP-gated channels, and that Ca2+ generates arachidonic acid via phospholipase D2 and diacylglycerol lipase rather than phospholipase A2. In contrast, dilation of arterioles depends on NMDA receptor activation and Ca2+-dependent NO generation by interneurons. These results reveal that different signaling cascades regulate cerebral blood flow at the capillary and arteriole levels.
Oxidative stress is involved in many hypertension-related vascular diseases in the brain, including stroke and dementia. Thus, we examined the role of genetic deficiency of NADPH oxidase subunit Nox2 in the function and structure of cerebral arterioles during hypertension. Arterial pressure was increased in right-sided cerebral arterioles with transverse aortic banding for 4 weeks in 8-week-old wild-type (WT) and Nox2-deficient (-/y) mice. Mice were given N(G)-nitro-L-arginine methyl ester (L-NAME, 10 mg/kg) or vehicle to drink. We measured the reactivity in cerebral arterioles through open cranial window in anesthetized mice and wall cross-sectional area and superoxide levels ex vivo. Aortic constriction increased systolic and pulse pressures in right-sided carotid arteries in all groups of mice. Ethidium fluorescence showed increased superoxide in right-sided cerebral arterioles in WT, but not in Nox2-/y mice. Dilation to acetylcholine, but not sodium nitroprusside, was reduced, and cross-sectional areas were increased in the right-sided arterioles in WT, but were unchanged in Nox2-/y mice. L-NAME reduced dilation to acetylcholine but did not result in hypertrophy in right-sided arterioles of Nox2-/y mice. In conclusion, hypertension-induced superoxide production derived from Nox2-containing NADPH oxidase promotes hypertrophy and causes endothelial dysfunction in cerebral arterioles, possibly involving interaction with nitric oxide.
Renal autoregulation consists of two main mechanisms; the myogenic response and the tubuloglomerular feedback mechanism (TGF). Increases in renal perfusion pressure activate both mechanisms causing a reduction in diameter of the afferent arteriole (AA) resulting in stabilization of the glomerular pressure. It has previously been shown that connexin-40 (Cx40) is essential in the renal autoregulation and mediates the TGF mechanism. The aim of this study was to characterize the myogenic properties of the AA in wild-type and connexin-40 knockout (Cx40KO) mice using both in situ diameter measurements and modeling. We hypothesized that absence of Cx40 would not per se affect myogenic properties as Cx40 is expressed primarily in the endothelium and as the myogenic response is known to be present also in isolated, endothelium-denuded vessels. Methods used were the isolated perfused juxtamedullary nephron preparation to allow diameter measurements of the AA. A simple mathematical model of the myogenic response based on experimental parameters was implemented. Our findings show that the myogenic response is completely preserved in the AA of the Cx40KO and if anything, the stress sensitivity of the smooth muscle cell in the vascular wall is increased rather than reduced as compared to the WT. These findings are compatible with the view of the myogenic response being primarily a local response to the local transmural pressure.
The present study aimed to investigate the role of propofol in mediating the vasomotor activity of the mesenteric arteriole (MA) of Sprague Dawley (SD) rats, and to elucidate the underlying mechanisms. The pressure myograph technique was used to examine the effect of different concentrations of propofol on the relaxation of blood vessels in the 2-3 mm MA segments freshly separated from the SD rats. The whole-cell patch-clamp technique was applied to observe the outward current of single vascular smooth muscle cells (VSMCs) obtained from the MAs of the SD rats. Furthermore, immunofluorescence was utilized to assess the expression of connexin (Cx) in the MAs of SD rats. The results indicated the following: i) Propofol relaxed the MA of SD rats in a concentration-dependent manner from 1×10-7 to 3×10-4 mol/l; ii) in the acutely dissociated VSMCs, propofol (1×10-7 to 3×10-4 mol/l) enhanced the outward current of VSMCs in a concentration-dependent manner; iii) the enhanced outward currents induced by propofol (1×10-5 mol/l) may be reversed by tetraethylammonium (TEA; 1 mmol/l), a calcium-activated K+ channel inhibitor; iv) the effect of propofol on the relaxation of the vasculature wAS reduced after perfusion with 1 mmol/l TEA; v) Cx40, Cx43 and Cx45 were expressed on the MA; 6) 18β-glycyrrhetintic acid and 2-aminoethoxydiphenyl borate, two types of gap junction blocker, inhibited the propofol-induced relaxation. The present study provides evidence that propofol relaxes the MA, which may be associated with its effect of enhancing the channel current of large-conductance calcium voltage-activated potassium channels, contributing to the K+ outflow and leading to VSMC hyperpolarization; the gap junction may facilitate the hyperpolarization, which may lead to vascular synchronized relaxation and thereby reduce the blood pressure.
1. Using the conventional whole-cell clamp method, the electrical responses of individual smooth muscle and endothelial cells to acetylcholine (ACh) were observed in multicellular preparations where the two types of cells remained in close apposition. 2. In both types of cells, ACh induced similar hyperpolarizing responses which, when recorded in current clamp mode, had two phases (an initial fast and a second slower phase). 3. After blocking gap junctions, including myoendothelial junctions, with 18beta-glycyrrhetinic acid, ACh induced an outward current with two phases in voltage-clamped endothelial cells. The outward current appeared around -90 mV and increased linearly with the membrane depolarization. 4. In smooth muscle cells, ACh failed to induce a membrane current after gap junctions had been blocked with 18beta-glycyrrhetinic acid. The inhibition of ACh-induced response by 18beta-glycyrrhetinic acid was observed using either sharp or patch electrodes. 5. Nominally Ca2+-free solution reduced the initial phase and abolished the second phase of ACh-induced responses of endothelial cells. Both phases were also reduced by charybdotoxin (CTX). 6. Our results indicate that in guinea-pig mesenteric arterioles, ACh hyperpolarizes endothelial cells by activating Ca2+-activated K+ channels which are sensitive to CTX. On the other hand, hyperpolarizing responses detected in smooth muscle cells seem to originate in endothelial cells and conduct to the muscle layer via myoendothelial gap junctions.
Ischaemic stroke patients treated with Selective Serotonin Reuptake Inhibitors (SSRI) show improved motor, cognitive and executive functions, but the underlying mechanism(s) are incompletely understood. Here, we report that cerebral arterioles in the rat brain superfused with therapeutically effective doses of the SSRI fluoxetine showed consistent, dose-dependent vasodilatation (by 1.2 to 1.6-fold), suppressible by muscarinic and nitric oxide synthase (NOS) antagonists [atropine, NG-nitro-l-arginine methyl ester (l-NAME)] but resistant to nicotinic and serotoninergic antagonists (mecamylamine, methylsergide). Fluoxetine administered 10-30 min. following experimental vascular photo-thrombosis increased arterial diameter (1.3-1.6), inducing partial, but lasting reperfusion of the ischaemic brain. In brain endothelial b.End.3 cells, fluoxetine induced rapid muscarinic receptor-dependent increases in intracellular [Ca(2+) ] and promoted albumin- and eNOS-dependent nitric oxide (NO) production and HSP90 interaction. In vitro, fluoxetine suppressed recombinant human acetylcholinesterase (rhAChE) activity only in the presence of albumin. That fluoxetine induces vasodilatation of cerebral arterioles suggests co-promotion of endothelial muscarinic and nitric oxide signalling, facilitated by albumin-dependent inhibition of serum AChE.
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