Increase In Intravascular Pressure Research Articles

BIN1 clusters CaV1.2 channels in vascular smooth muscle

Resistance vessel such as mesenteric arteries respond to increases in intravascular pressure by constricting. Ca2+ influx via voltage‐gated CaV1.2 channels in the smooth muscle surrounding these vessels is critical for the development of myogenic tone and thus the regulation of arterial dimeter and blood flow. Our group discovered that CaV1.2 channels have an inherent ability to form clusters and functionally couple in response to local elevations in [Ca2+]i. The consequence of these channels coming together is that they amplify Ca2+ influx during depolarization. However, the mechanisms dictating the arrangement of CaV1.2 channels in smooth muscle cells are unknown. BIN1, a member of the BAR (Bin1‐Amphiphysin‐Rvs) domain superfamily, has been implicated in the trafficking of CaV1.2 channels but has not yet been studied in smooth muscle. In this study, we test the hypothesis that BIN1 promotes the formation of CaV1.2 clusters enhancing overall Ca2+ influx into the vascular smooth muscle and shaping arterial diameter. We report that BIN1 is expressed and translated in arterial smooth muscle while ground state depletion (GSD) super‐resolution imaging suggest that smooth muscle specific down‐regulation of BIN1 diminishes CaV1.2 cluster formation. Using patch clamp electrophysiology and pressurized arteriography, we observed that loss of BIN1 substantially diminishes ICa and attenuates arterial tone. Overall, these results suggest that BIN1 is a critical component in shaping CaV1.2 clustering and plays a physiological role in vascular smooth muscle Ca2+ entry and arterial diameter.Support or Funding InformationThis work is supported by NIH R01 HL085870 (LFS), T32GM099608 (SO), and 18PRE33960249 (SO)This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Vasoconstrictor stimulus determines the functional contribution of myoendothelial feedback to mesenteric arterial tone.

In isolated resistance arteries, endothelial modulation of vasoconstrictor responses to α1 -adrenoceptor agonists occurs via a process termed myoendothelial feedback: localized inositol trisphosphate (InsP3 )-dependent Ca2+ transients activate intermediate conductance Ca2+ -activated K+ (IKCa ) channels, hyperpolarizing the endothelial membrane potential to limit further reductions in vessel diameter. We demonstrate that IKCa channel-mediated myoendothelial feedback limits responses of isolated mesenteric arteries to noradrenaline and nerve stimulation, but not to the thromboxane A2 mimetic U46619 or to increases in intravascular pressure. In contrast, in the intact mesenteric bed, although responses to exogenous noradrenaline were limited by IKCa channel-mediated myoendothelial feedback, release of NO and activation of endothelial small conductance Ca2+ -activated K+ (SKCa ) channels in response to increases in shear stress appeared to be the primary mediators of endothelial modulation of vasoconstriction. We propose that (1) the functional contribution of myoendothelial feedback to arterial tone is determined by the nature of the vasoconstrictor stimulus, and (2) although IKCa channel-mediated myoendothelial feedback may contribute to local control of arterial diameter, in the intact vascular bed, increases in shear stress may be the major stimulus for engagement of the endothelium during vasoconstriction. Constriction of isolated resistance arteries in response to α1 -adrenoceptor agonists is limited by reciprocal engagement of inhibitory endothelial mechanisms via myoendothelial feedback. In the current model of feedback, agonist stimulation of smooth muscle cells results in localized InsP3 -dependent Ca2+ transients that activate endothelial IKCa channels. The subsequent hyperpolarization of the endothelial membrane potential then feeds back to the smooth muscle to limit further reductions in vessel diameter. We hypothesized that the functional contribution of InsP3 -IKCa channel-mediated myoendothelial feedback to limiting arterial diameter may be influenced by the nature of the vasoconstrictor stimulus. To test this hypothesis, we investigated the functional role of myoendothelial feedback in modulating responses of rat mesenteric resistance arteries to the adrenoceptor agonist noradrenaline, the thromboxane A2 mimetic U46619, increases in intravascular pressure and stimulation of perivascular sympathetic nerves. In isolated arteries, responses to noradrenaline and stimulation of sympathetic nerves, but not to U46619 and increases in intravascular pressure, were modulated by IKCa channel-dependent myoendothelial feedback. In the intact mesenteric bed perfused under conditions of constant flow, responses to exogenous noradrenaline were modulated by myoendothelial feedback, but shear stress-induced release of NO and activation of endothelial SKCa channels appeared to be the primary mediators of endothelial modulation of vasoconstriction to agonists and nerve stimulation. Thus, we propose that myoendothelial feedback may contribute to local control of diameter within arterial segments, but at the level of the intact vascular bed, increases in shear stress may be the major stimulus for engagement of the endothelium during vasoconstriction.

Varicose veins of the small pelvis and pelvic congestion syndrome. A differentiated approach: the choice of method of contraception, treatment, prevention

The article considers the main points that affect the quality of life of women with varicose veins of small pelvis with congestion and without it, in particular the use of hormonal methods of contraception, and also discussed the issues of diagnostics, prevention and treatment of these diseases. Algorithms of clinical tactics for conducting such patients are presented. Particular attention is focused on the features of the appointment of hormonal drugs in this category of women. You can determine the methods of treatment and avoid long-term unreasonable prescription of various medicine (especially hormones that will mask or worsen the course of the disease) if you select groups of women with varicose veins of the small pelvis without congestion and with it (reflux).Varicose veins of the small pelvis and pelvic congestion syndrome are conditions that require an interdisciplinary and differentiated approach. Symptoms of these conditions can be put on a mask of various gynecological, urological, traumatological diseases. Anatomical and physiological features of the structure of the veins and the regulation of their venous tone explain the possibility of forming a venous congestive syndrome in women. This can be due to two reasons: due to the violation of the outflow of venous blood or due to the obstruction of any vein of the ovary, any increase in intravascular pressure not controlled by the venous tone at the level of the pelvis.Varicose veins of the small pelvis and pelvic congestion syndrome remain unexplored until the end. There are no uniform standards for their diagnostics. Varicose veins of the small pelvis and pelvic congestion syndrome are different diseases which requiring an understanding of the mechanisms of their development and consequences. If a pelvic varicose veins are suspected, the first diagnostic test is usually ultrasound. Modern ultrasound technique can evaluate blood flow in various veins. To study the blood flow in the veins, laparoscopy, venography in combination with CT or MRI can also be performed.

Local control of TRPV4 channels by AKAP150-targeted PKC in arterial smooth muscle

Arterial myocytes have the intrinsic ability to contract in response to increases in intravascular pressure (Bayliss, 1902). It has been proposed that this myogenic response is initiated by the stretch-induced activation of the nonselective cation channels TRPP2, TRPC6, and TRPM4, which depolarize arterial myocytes (Welsh et al., 2002; Earley et al., 2004; Spassova et al., 2006; Narayanan et al., 2013). Membrane depolarization activates voltage-gated L-type CaV1.2 channels (Harder et al., 1987; Fleischmann et al., 1994; Rubart et al., 1996; Jaggar et al., 1998). The influx of Ca via a single CaV1.2 channel can be optically detected in the form of a “CaV1.2 sparklet” (Navedo et al., 2005; Amberg et al., 2007). Simultaneous activation of multiple CaV1.2 sparklets induces a cell-wide increase in intracellular Ca ([Ca]i) that activates myosin light chain kinase and thus triggers contraction. This myogenic

Contribution of Kv7.4/Kv7.5 Heteromers to Intrinsic and Calcitonin Gene-Related Peptide–Induced Cerebral Reactivity

Middle cerebral artery (MCA) diameter is regulated by inherent myogenic activity and the effect of potent vasodilators such as calcitonin gene-related peptide (CGRP). Previous studies showed that MCAs express KCNQ1, 4, and 5 potassium channel genes, and the expression products (Kv7 channels) participate in the myogenic control of MCA diameter. The present study investigated the contribution of Kv7.4 and Kv7.5 isoforms to myogenic and CGRP regulation of MCA diameter and determined whether they were affected in hypertensive animals. Isometric tension recordings performed on MCA from normotensive rats produced CGRP vasodilations that were inhibited by the pan-Kv7 channel blocker linopirdine (P<0.01) and after transfection of arteries with siRNA against KCNQ4 (P<0.01) but not KCNQ5. However, isobaric myography revealed that myogenic constriction in response to increases in intravascular pressure (20-80 mm Hg) was affected by both KCNQ4 and KCNQ5 siRNA. Proximity ligation assay signals were equally abundant for Kv7.4/Kv7.4 or Kv7.4/Kv7.5 antibody combinations but minimal for Kv7.5/Kv7.5 antibodies or Kv7.4/7.1 combinations. In contrast to systemic arteries, Kv7 function and Kv7.4 abundance in MCA were not altered in hypertensive rats. This study reveals, for the first time to our knowledge, that in cerebral arteries, Kv7.4 and Kv7.5 proteins exist predominantly as a functional heterotetramer, which regulates intrinsic myogenicity and vasodilation attributed to CGRP. Surprisingly, unlike systemic arteries, Kv7 activity in MCAs is not affected by the development of hypertension, and CGRP-mediated vasodilation is well maintained. As such, cerebrovascular Kv7 channels could be amenable for therapeutic targeting in conditions such as cerebral vasospasm.

CEREBRAL VASCULAR DYSFUNCTION FOLLOWING TRAUMATIC BRAIN INJURY

Traumatic brain injury (TBI) affects more than 1.7 million people in the United States annually, having a major impact on public health. Cerebral autoregulation is altered in humans after TBI and in animal models, reflecting a fundamental loss of pressure‐induced cerebral artery constriction (myogenic tone). We hypothesize that TBI leads to abnormal increases in endothelial nitric oxide (NO) synthesis leading to decreased cerebral vascular tone. A fluid percussion model of brain injury was used to produce moderate TBI in adult Sprague‐Dawley rats and animals were studied 24 h after injury. Magnetic resonance imaging (MRI) demonstrated brain damage and edema involving both the ipsilateral and contralateral sides of the cerebral cortex. Cerebral arteries from TBI animals exhibited decreased cytosolic smooth muscle (SM) Ca2+ and reduced myogenic tone in response to stepwise increases in intravascular pressure compared to controls. Inhibition of NO synthase with Nω‐L‐arginine (L‐NNA) restored myogenic tone and SM Ca2+ in arteries from TBI animals. Bioavailability of NO assessed via 4,5‐diaminofluorescein (DAF‐2 DA) was increased in cerebral artery endothelium of TBI animals compared to controls. These results suggest that enhanced nitric oxide‐mediated vasodilation contributes to loss of myogenic tone and cerebrovascular dysfunction following TBI; this information may ultimately lead to novel therapeutic targets that improve clinical outcomes.

Original article Disturbed regulation of the isolated middle cerebral artery in acute hyponatremia

Hyponatremia is a common disorder of water-electrolyte balance characterized by the decrease of plasma sodium ions concentration below 135 mM. Although water-electrolyte balance is regulated by a kidney, symptoms of hyponatremia are related to the disturbances of intracranial homeostasis and are attributed to brain swelling. Despite the importance of blood vessels function for the homeostasis of the brain, little is known about the influence of hyponatremia on cerebrovascular regulation. In the present study isolated, perfused and pressurized rat middle cerebral arteries (MCAs) were subjected to hyponatremia in the organ chamber by lowering the concentration of sodium ions from 145 to 121 mM. The response of the MCAs to the changes in intravascular pressure and to endothelium-dependent and independent vasodilators was compared in normo- and hyponatremia. The following results were obtained: the contraction of the MCA during progressive increases in intravascular pressure was similar in normo- and hyponatremia; the dilation in response to acetylcholine (10-6 M, 10-5 M and 10-4 M), which is endothelium- and nitric oxide-dependent, was severely impaired in hyponatremia; the contraction after administration of the nonselective inhibitor of nitric oxide synthesis - NG-nitro-L-arginine methyl ester (L-NAME, 10-5 M) was similar in normo- and hyponatremia; the nitric oxide donor - S-nitroso-N-acetylpenicillamine (SNAP, 10-5 M) dilated MCA only in normonatremia. The results of this study show that myogenic response and shear stress-dependent relaxation of the MCA are not affected by acute hyponatremia. However, agonist-stimulated, endothelial nitric oxide synthase (eNOS)-mediated relaxation is severely impaired which is associated with a decreased smooth muscle response to nitric oxide (NO). In conclusion, our results demonstrate that the regulation of isolated middle cerebral artery is impaired in acute hyponatremia which may contribute to the disturbance of intracranial homeostasis associated with hyponatremia.

Tricuspid valve chordal rupture due to airbag injury and review of pathophysiological mechanisms

Blunt trauma to the chest is associated with significant morbidity and mortality. The latter is usually due to an aortic transection, whereas the former is related to myocardial contusion, cardiac valve injury, coronary artery disruption and intracardiac shunts due to the formation of septal defects. The main mechanisms causing these injuries are due to the sudden deceleration force and compression within the chest cavity. Moreover, there is also the sudden increase in intravascular pressure due to a mechanical compression effect and a hormonal adrenergic surge during the event. We report a case of a tricuspid valve injury caused by the deployment of the airbag during a high-speed impact car accident and the subsequent damage to the tricuspid valve chordal mechanism. The patient's management and the pathophysiological mechanisms involved in the injury are reviewed.

Organ culture as an in vitro model for the study of dual‐specificity phosphatase‐5 (DUSP‐5) and myogenic response in rat cerebral arterioles

Increase in intravascular pressure causes depolarization and constriction of cerebral arteries. The molecular mechanism of pressure‐induced myogenic response remains obscure. Our goal was to provide an optimal time window and preserved vascular function for an organ culture of cerebral arteries for the study of mechanisms involved in the regulation of cerebral arterial function. We initiated a comparative study of cultured and freshly isolated cerebral arteries in response to elevated intravascular pressure, vasodilator and vasoconstrictor stimuli, activity of Ca2+‐activated K+ (KCa) single‐channel current and protein expression of CYP 4 and DUSP‐5 enzymes. The results indicate that 72 h time frame of organ culture of cerebral arteries maintains cellular integrity, pressure dependent constriction, CYP4A2 and 4F protein expression, endothelium‐dependent and independent dilations, KCa channel current activity and vasoconstrictor response to serotonin. Furthermore, using a permeabilization, transfection technique the 72 h cultured arteries elicited a gene specific siRNA induced knockdown of DUSP‐5 protein expression. Subsequent pressure myograph studies and inhibitor studies revealed role of DUSP‐5 in regulation of myogenic tone. We propose a possible mechanism by which DUSP‐5 and ERK regulate myogenic response in cerebral arterioles. RO1 HL033833, RO1 HL092105, T32 HL007792.

The knack of resisting increases in intravascular pressure: the potential role for epithelial Na+ channel protein subunits in arterial myogenic reactivity

The knack of resisting increases in intravascular pressure: the potential role for epithelial Na⁺ channel protein subunits in arterial myogenic reactivity

Endothelium‐dependent modulation of cerebral artery myogenic tone by cyclopiazonic acid

The myogenic response, the ability of cerebral arteries to constrict in response to increases in intra‐vascular pressure, is a key autoregulatory mechanism by which cerebral blood flow is maintained within narrow limits despite large changes in pressure. The endothelium modulates arterial diameter via the release of factors such as nitric oxide (NO) and by electrical coupling with smooth muscle cells. We hypothesized that disruption of endothelial intracellular Ca2+ stores will affect the cerebral artery myogenic response. In endothelium‐intact middle cerebral arteries, cyclopiazonic acid (CPA; 10 μM) and thapsigargin (500 nM), inhibitors of the sarcoplasmic Ca2+‐ATPase (SERCA), each inhibited development of myogenic tone, e.g. 80mmHg, tone development was reduced by 65.5 ± 6.0% (n=6). In endothelium‐denuded arteries, CPA and thapsigarin had no effect the myogenic response. In endothelium‐intact arteries, L‐NG‐nitroarginine methyl ester (100 mM), an inhibitor of NO synthase, did not affect the CPA‐induced loss of myogenic response but addition of apamin (50nM) and Tram‐34 (1 μM), inhibitors of endothelial small and intermediate conductance Ca2+‐activated potassium (KCa) channels, prevented the effect of CPA. These data indicate that inhibition of endothelial SERCA leads to the activation of KCa channels and loss of cerebral myogenic tone. Supported by HSFC.

Effects of H&lt;sub&gt;2&lt;/sub&gt;S on Myogenic Responses in Rat Cerebral Arterioles

The potential biological significance of hydrogen sulfide (H₂S) has attracted growing interests in recent years, but its role in the myogenic response of rat cerebral arterioles has not been explored. Rats were injected with NaHS (an H₂S donor, 2-200 µmol·kg⁻¹·day⁻¹, i.p.) or saline for 3 weeks. MBP was measured with a tail-cuff method. Cerebral arterioles were isolated and cannulated in an organ bath system, and vessel diameters were measured with an image-shearing device. Changes in diameter in response to stepwise increases in intravascular pressure (20-120 mmHg) were investigated under no-flow conditions. After the treatments, plasma H₂S increased and MBP decreased significantly. NaHS reduced the myogenic response in a dose-dependent manner. This effect was markedly attenuated by glibenclamide, a K(ATP) channel blocker. Blockade of nitric oxide (NO) production with NG-nitro-L-arginine methyl ester (L-NAME, a NO synthase inhibitor) enhanced, whereas removal of the endothelium abolished the inhibitory role of NaHS on the myogenic response. For the first time it has been demonstrated that H₂S decreases the myogenic response of cerebral arterioles in vivo, and this effect is endothelium-dependent and partially mediated by K(ATP) channels.

ポリープ状脈絡膜血管症

Polypoidal choroidal vasculopathy (PCV) is characterized by a branching vascular network with polypoidal lesions under the retinal pigment epithelium (RPE). In Japan, it is classified as a specific form of exudative age-related macular degeneration. However, several issues which we investigated regarding the pathogenesis and treatment of PCV remain unresolved. We investigated the pathogenesis, clinical findings and treatment of PCV. 1. Indocyanine green angiographic findings. There were two different patterns on indocyanine green angiograms. In the first pattern, both feeder and draining vessels were visible and network vessels showed characteristic findings of choroidal neovascularization (CNV). Points of focal dilatation on marginal vessels were comprised of polypoidal lesions. In the second pattern, neither feeder nor draining vessels were visible and there were few network vessels. The points of deformation of network vessels appeared to be polypoidal lesions. The former represents a deformation of CNV, i.e. polypoidal CNV; the latter is thought to result from abnormalities of the choroidal vessels, i.e. PCV in the strict sense. 2. Pathological findings of PCV in the strict sense. The histopathological characteristics of PCV in the strict sense, which had been eliminated by vitrectomy, were dilatation and hyalinization of vessels, massive exudative changes in blood plasma, basement membrane-like deposits and scant granulomatous tissue. These vessels were located beneath Bruch's membrane. The findings indicate that PCV in the strict sense arises from hyalinized arteriolosclerosis of choroidal vessels. 3. Optical coherence tomographic findings. A break was found in the high reflective line which revealed Bruch's membrane. Low reflective tissue was observed at the break corresponding to a feeder vessel. The high reflective line which corresponded to the retinal pigment epithelium was uneven, and highly elevated portions of the RPE corresponded to thick network vessels and polypoidal lesions. Feeder vessels are thought to invade via Bruch's membrane to form network vessels and polypoidal lesions at the termini of the network vessels, both of which push the RPE upward. Therefore, polypoidal CNV is thought to represent a deformation of the CNV under the RPE. In PCV in the strict sense, an irregular thickened line with highly reflective substances adhering to the lower portion of it, curved downward corresponding to the site at which the network vessel filling began. A dimple in the RPE was observed which paralleled the curve of the line. The RPE was pushed upward, corresponding to the network vessels. Judging from the results of histopathological studies, abnormal vessels may be pushed up the RPE secondary to an increase in intravascular pressure due to the presence of several dilated vessels and by massive exudation from these vessels within the choroid at network vessels. The dimple in the RPE might be attributable to intra-choroidal pressure being decreased at the point at which network vessel filling began. 4. Genetic findings. There were significant differences in all distributions of ARMS 2 (A69S) between the polypoidal CNV and control groups. In contrast, the distribution of ARMS 2 (A69S) did not differ between the PCV in the strict sense group and the control group. The ARMS 2 (A69S) gene is closely related to age-related macular degeneration. Polypoidal CNV was thought to be associated with age-related macular degeneration. 5. Treatment of subfoveal PCV. Mean visual acuity improved 1 year after photodynamic therapy (PDT). Good visual acuity, small lesion size of the network of vessels with polypoidal lesions, and the absence of subfoveal polypoidal lesions were pre-PDT predictors that corresponded to the improvement in vision. However, mean visual acuity had decreased to a level similar to that prior to PDT at 2 and 3 years after treatment. In PCV in the strict sense, the branching vascular network persisted after PDT, and polypoidal lesions frequently recurred at the termini. The branching vascular network sometimes expanded and was accompanied by polypoidal CNV or classic CNV. These results indicate that repeated PDT, as monotherapy, has limitations as a long-term treatment for PCV in the strict sense. Intravitreal injection of ranibizumab for eyes with a visual acuity of 0.6 or more, which is not a good indication for PDT, achieved improvement in mean visual acuity 1 year after the treatment, though the frequency of polypoidal lesion regression was low. This procedure seems to be useful for eyes with good visual acuity for a period of at least one year. 6. Conclusion. Using indocyanine green angiography, optical coherence tomography and genetic testing, PCV was classified into 2 groups, polypoidal CNV and PCV in the strict sense. PCV in the strict sense was characterized by arteriolsclerosis histopathologically. Polypoidal CNV is thought to represent deformation of CNV under the RPE in age-related macular degeneration, while PCV in the strict sense is thought to be due to choroidal vessel abnormalities. The long-term efficacy of repeated PDT as monotherapy, for subfoveal PCV was limited. Further evaluation is necessary to establish a treatment algorithm for PCV.

Intracellular calcium stores contribute to the myogenic response of rat cerebral arteries

Cerebral blood flow is controlled by autoregulatory mechanisms which maintain blood flow within narrow limits despite large changes in blood pressure. Increases in blood pressure cause small cerebral arteries to constrict, a mechanism called the myogenic response. We investigated the contribution of intracellular calcium stores to the development of myogenic tone in rat middle cerebral arteries.Cerebral arteries mounted in a pressure myograph were subjected to stepwise increases in intra‐vascular pressure (20–120 mmHg), and changes in vessel diameter were recorded in the presence or absence of drugs. Cyclopiazonic (CPA; 10 μM), an inhibitor of the SR Ca2+‐ATPase, attenuated myogenic tone at 80mmHg by 64.2 ± 7.2% (n=5). Caffeine (10 mM), a ryanodine channel opener, reduced myogenic tone by 80.3 ± 6.7% (n=5). The effect of caffeine was not inhibited by iberiotoxin (IBTX 100nM; n=4), a large conductance calcium‐activated potassium channel (BKCa) blocker, suggesting that activation of BKCa is unlikely. When CPA was added in combination with nifedipine (10 μM), an L‐type calcium channel blocker, development of myogenic tone was abolished. In conclusion, our data suggests that release of intracellular calcium from the SR plays an important role in the development of myogenic tone in rat middle cerebral arteries. Funded by Heart and Stroke Foundation and University of Alberta Queen Elizabeth II Award.

High Intravascular Pressure Attenuates Vascular Dilation Responses of Small Mesenteric Arteries in the Rat

Alterations in intravascular pressure can affect vascular function and the morphological properties of arteries. Although it has been shown that a transient elevation of blood pressure impairs endothelium-dependent dilation in small arteries, the vascular dilation responses during high intravascular pressure have not yet been investigated. Using pressure myography, the endothelium-dependent and -independent dilation responses of small mesenteric arteries of rats were examined under 3 different intravascular pressure conditions (50, 80 and 120 mmHg). Endothelium-dependent dilation was evaluated by measuring vasodilator responses to increasing doses of acetylcholine (ACh, 10(-9) to 10(-4) mol/L) or increases in intraluminal flow (7-36 microl/min). Endothelium-independent vasodilator function was examined by using sodium nitroprusside (SNP, 10(-9) to 10(-4) mol/L). Flow-mediated dilation was significantly attenuated at 120 mmHg whereas ACh-induced dilation was progressively decreased with increases in intravascular pressure (at 80 and 120 mmHg). Significant attenuation in the vasodilator response to SNP was also observed at 80 and 120 mmHg. Endothelium-dependent and-independent dilation responses are progressively attenuated with acute increases in intravascular pressure.

Are intramural suction-squeezing effects generated by the variations in radial wall stress during each heart beat the motor of atherosclerosis? A new concept

In the early sixties, the existence of predilection sites for atherosclerotic lesions inside the arterial circulation led to the concept that low wall shear stress (WSS) was responsible, together with systemic factors like high blood pressure, hypercholesterolemia, or diabetes, for the genesis and progression of atherosclerosis. It was found later that oscillating WSS and high WSS gradients could also be incriminated. Yet, this concept, which is broadly accepted today, fails to explains several facts, for instance that some arteries (e.g. epicardial coronary arteries) are more prone to become atherosclerotic than other ones exposed to the same systemic factors (e.g. hepatic and brain arteries). In this paper, we present a quite different concept. It is based on the fact that the increase in intravascular pressure and flow that occur in the arteries during systole generates, at the predilection sites of atherosclerotic lesions (bends, bifurcations, and branchings), an increase of radial wall stress in the outer layers of the arterial wall so that this stress becomes momentarily tensile. These cyclic stress increases have a suction effect that is likely to facilitate the diffusion of atherogenic cells and substances inside the wall. Furthermore, since arteries are not primarily structured to resist inversions of radial stress, they may also create damages (e.g. disruptions of cell membranes and elastic lamellae) followed by inflammations and micro-haemorrhages in the wall. This new concept may provide a complementary (or possibly alternative) explanation of atherosclerosis.

Management of pulmonary hypertension: physiological and pharmacological considerations for anesthesiologists.

For decades the pulmonary circulation was not considered as important as the systemic (“greater”) circulation. However, pulmonary hypertension can arise because of many diseases of the heart and lung. Therefore, increasing efforts in research have been undertaken leading to a profound increase in un

The arteriovenous fistula.

The ground-breaking article by Brescia and Cimino in 1966 ([1][1]) revolutionized the creation of the vascular access, and the Cimino fistula was soon used in almost all dialysis patients. Unfortunately, subsequent wide-spread use of PTFE grafts instead of AV fistulae occurred because of the ease of

Molecular and cellular basis of pulmonary vascular remodeling in pulmonary hypertension

Clinical pulmonary hypertension is characterized by a sustained elevation in pulmonary arterial pressure. Pulmonary vascular remodeling involves structural changes in the normal architecture of the walls of pulmonary arteries. The process of vascular remodeling can occur as a primary response to injury, or stimulus such as hypoxia, within the resistance vessels of the lung. Alternatively, the changes seen in more proximal vessels may arise secondary to a sustained increase in intravascular pressure. To withstand the chronic increase in intraluminal pressure, the vessel wall becomes thickened and stronger. This “armouring” of the vessel wall with extra-smooth muscle and extracellular matrix leads to a decrease in lumen diameter and reduced capacity for vasodilatation. This maladaptive response results in increased pulmonary vascular resistance and consequently, sustained pulmonary hypertension. The process of pulmonary vascular remodeling involves all layers of the vessel wall and is complicated by the finding that cellular heterogeneity exists within the traditional compartments of the vascular wall: intima, media, and adventitia. In addition, the developmental stage of the organism greatly modifies the response of the pulmonary circulation to injury. This review focuses on the latest advances in our knowledge of these processes as they relate to specific forms of pulmonary hypertension and particularly in the light of recent genetic studies that have identified specific pathways involved in the pathogenesis of severe pulmonary hypertension. Copyright 2002, Elsevier Science (USA). All rights reserved.

Openings in frog microvascular endothelium at different rates of increase in pressure and at different temperatures.

Experiments were carried out on single mesenteric capillaries and venules of pithed frogs to determine whether the rate of increase in intravascular pressure (dP/dt) influenced the critical pressure (P(B)) which increases wall permeability. Vessels, microperfused with frog Ringer solutions containing 0.1% bovine serum albumin and red cells, were occluded downstream before pressure was raised either as a ramp or in a series of 13.6 cmH2O steps. By varying step duration, the mean dP/dt could be matched to dP/dt applied as a steady ramp. P(B) was recorded as the pressure at which there was an abrupt increase in filtration with red cells passing to and through one or more sites in the vessel wall. In all vessels, increasing dP/dt raised P(B), with no differences between steps and ramps. The relation between P(B) and dP/dt was linear, consistent with a latent period, T (the slope), between a critical pressure being reached and the abrupt increase in permeability being observed. Direct observation confirmed this latent period. Between 12 and 20 (o)C, T was 8.5 +/- 0.47 s; between 0 and 5 degrees C, T was 11.5 +/- 0.97 s. Tissue cooling did not influence the time constant, tau, describing the rate of stretch of wall following a step increase in pressure and used to measure wall visco-elastic properties. Nor was the value of tau (1.15 +/- 0.06 s, n = 42) consistent with T being accounted for by visco-elasticity. It is suggested that the latent period may indicate an active response of the endothelium.