Stretch-Induced Intimal Failure in Isolated Cerebral Arteries as a Function of Development.

Recent clinical studies have shown that traumatic brain injury is a significant risk factor for stroke. Motivated to better understand possible mechanisms of this association, we studied subfailure disruption of the intima in overstretched sheep cerebral arteries, as this has been implicated in the increased risk of stroke following blunt cerebrovascular injury. Middle cerebral arteries from four age groups (ranging from fetal to adult) were stretched axially to failure, and intimal disruption was captured with a video camera. All vessels demonstrated intimal disruption prior to catastrophic failure, with nearly all incurring disruption at stretch values well below those at ultimate stress (means of 1.56 and 1.73, respectively); the lowest stretch associated with intimal disruption was 1.29. The threshold of intimal failure was independent of age. Additional analysis showed that disruption included failure of both the endothelium and internal elastic lamina. Although our experiments were conducted at quasi-static rates, the results likely have important implications for vessel function following trauma. Future work should seek to identify subfailure disruption of the cerebrovasculature in head trauma.

Large conductance voltage- and calcium-gated potassium channels (BK) in cerebral artery myocytes of perinatal fetal primates share several major characteristics with the adult phenotype.

Large conductance voltage- and calcium-gated channels (BK) control fundamental processes, including smooth muscle contractility and artery diameter. We used a baboon (Papio spp) model of pregnancy that is similar to that of humans to characterize BK channels in the middle cerebral artery and its branches in near-term (165 dGa) primate fetuses and corresponding pregnant mothers. In cell-attached patches (K+pipette = 135 mM) on freshly isolated fetal cerebral artery myocytes, BK currents were identified by large conductance, and voltage- and paxilline-sensitive effects. Their calcium sensitivity was confirmed by a lower Vhalf (transmembrane voltage needed to reach half-maximal current) in inside-out patches at 30 versus 3 µM [Ca2+]free. Immunostaining against the BK channel-forming alpha subunit revealed qualitatively similar levels of BK alpha protein-corresponding fluorescence in fetal and maternal myocytes. Fetal and maternal BK currents recorded at 3 µM [Ca2+]free from excised membrane patches had similar unitary current amplitude, and Vhalf. However, subtle differences between fetal and maternal BK channel phenotypes were detected in macroscopic current activation kinetics. To assess BK function at the organ level, fetal and maternal artery branches were pressurized in vitro at 30 mmHg and probed with the selective BK channel blocker paxilline (1 µM). The degree of paxilline-induced constriction was similar in fetal and maternal arteries, yet the constriction of maternal arteries was achieved sooner. In conclusion, we present a first identification and characterization of fetal cerebral artery BK channels in myocytes from primates. Although differences in BK channels between fetal and maternal arteries exist, the similarities reported herein advance the idea that vascular myocyte BK channels are functional near-term, and thus may serve as pharmacological targets during the perinatal-neonatal period.

Effect of healthy aging and sex on middle cerebral artery blood velocity dynamics during moderate-intensity exercise.

Blood velocity measured in the middle cerebral artery (MCAV) increases with finite kinetics during moderate-intensity exercise, and the amplitude and dynamics of the response provide invaluable insights into the controlling mechanisms. The MCAV response after exercise onset is well fit to an exponential model in young individuals but remains to be characterized in their older counterparts. The responsiveness of vasomotor control degrades with advancing age, especially in skeletal muscle. We tested the hypothesis that older subjects would evince a slower and reduced MCAV response to exercise. Twenty-nine healthy young (25 ± 1 yr old) and older (69 ± 1 yr old) adults each performed a rapid transition from rest to moderate-intensity exercise on a recumbent stepper. Resting MCAV was lower in older than young subjects (47 ± 2 vs. 64 ± 3 cm/s, P < 0.001), and amplitude from rest to steady-state exercise was lower in older than young subjects (12 ± 2 vs. 18 ± 3 cm/s, P = 0.04), even after subjects were matched for work rate. As hypothesized, the time constant was significantly longer (slower) in the older than young subjects (51 ± 10 vs. 31 ± 4 s, P = 0.03), driven primarily by older women. Neither age-related differences in fitness, end-tidal CO2, nor blood pressure could account for this effect. Thus, MCAV kinetic analyses revealed a marked impairment in the cerebrovascular response to exercise in older individuals. Kinetic analysis offers a novel approach to evaluate the efficacy of therapeutic interventions for improving cerebrovascular function in elderly and patient populations. NEW & NOTEWORTHY Understanding the dynamic cerebrovascular response to exercise has provided insights into sex-related cerebrovascular control mechanisms throughout the aging process. We report novel differences in the kinetics response of cerebrovascular blood velocity after the onset of moderate-intensity exercise. The exponential increase in brain blood flow from rest to exercise revealed that 1) the kinetics profile of the older group was blunted compared with their young counterparts and 2) the older women demonstrated a slowed response.

Aging modifies the effect of cardiac output on middle cerebral artery blood flow velocity.

An association between cerebral blood flow (CBF) and cardiac output (CO) has been established in young healthy subjects. As of yet it is unclear how this association evolves over the life span. To that purpose, we continuously recorded mean arterial pressure (MAP; finger plethysmography), CO (pulse contour; CO-trek), mean blood flow velocity in the middle cerebral artery (MCAV; transcranial Doppler ultrasonography), and end-tidal CO2 partial pressure (PetCO2) in healthy young (19-27 years), middle-aged (51-61 years), and elderly subjects (70-79 years). Decreases and increases in CO were accomplished using lower body negative pressure and dynamic handgrip exercise, respectively. Aging in itself did not alter dynamic cerebral autoregulation or cerebrovascular CO2 reactivity. A linear relation between changes in CO and MCAVmean was observed in middle-aged (P < 0.01) and elderly (P = 0.04) subjects but not in young (P = 0.45) subjects, taking concurrent changes in MAP and PetCO2 into account. These data imply that with aging, brain perfusion becomes increasingly dependent on CO.

Angiographic Morphometry of Internal Carotid Artery Circulation in Turkish Children.

AIM: Knowledge of cerebrovascular morphology is integral in planning neuroendovascular interventions, especially for procedures involving placement of stents, flow diverters or stentrievers. There is insufficient data on angiographic normative values of cerebral circulation in the pediatric age group since angiograms are uncommonly performed in children except for arteriovenous malformations in which arterial dimensions are larger than normal. We aimed to measure the diameters of internal carotid circulation (ICC) arteries on digital subtraction angiograms of pediatric patients and determine the growth trends. MATERIAL AND METHODS: This is a retrospective cross-sectional study measurements of ICC arteries of 64 pediatric patients (4-122 months) with retinoblastoma undergoing intra-arterial chemotherapy. RESULTS: Petrous, cavernous, supraclinoid and choroidal segments of internal carotid artery (ICA) and anterior cerebral artery (ACA) diameters had significant correlation with age. Most of the growth was noted in the first 36-48 months of life. Middle cerebral artery (MCA) diameter did not show significant correlation with age. 87% of the adult diameter of the MCA was attained in the first 6 months of life. ICC arteries reached 81% to 99% of adult sizes in the first 48 months of life. On the contrary, the main iliac artery was only 59% of the adult diameter at this age group. CONCLUSION: Use of current intracranial stents in children appears tolerable due to the growth pattern of ICC arteries. Based on this data, the current armamentarium of intracranial stents or stent-like devices is sufficient to cover the need in the pediatric population.

Age, aerobic fitness, and cerebral perfusion during exercise: role of carbon dioxide.

Middle cerebral artery mean velocity (MCAvmean) is attenuated with increasing age both at rest and during exercise. The aim of this study was to determine the influence of the age-dependent reduction in arterial Pco2 (PaCO2) and physical fitness herein. We administered supplemental CO2 (CO2 trial) or no additional gas (control trial) to the inspired air in a blinded and randomized manner, and assessed middle cerebral artery mean flow velocity during graded exercise in 1) 21 young [Y; age 24 ± 3 yr (±SD)] volunteers of whom 11 were trained (YT) and 10 considered untrained (YUT), and 2) 17 old (O; 66 ± 4 yr) volunteers of whom 8 and 9 were considered trained (OT) and untrained (OUT), respectively. A resting hypercapnic reactivity test was also performed. MCAvmean and PaCO2 were lower in O [44.9 ± 3.1 cm/s and 30 ± 1 mmHg (±SE)] compared with Y (59.3 ± 2.3 cm/s and 34 ± 1 mmHg, P < 0.01) at rest, independent of aerobic fitness level. The age-related decreases in MCAvmean and PaCO2 persisted during exercise. Supplemental CO2 reduced the age-associated decline in MCAvmean by 50%, suggesting that PaCO2 is a major component in the decline. On the other hand, relative hypercapnic reactivity was neither influenced by age (P = 0.46) nor aerobic fitness (P = 0.36). Although supplemental CO2 attenuated exercise-induced reduction in cerebral oxygenation (near-infrared spectroscopy), this did not influence exercise performance. In conclusion, PaCO2 contributes to the age-associated decline in MCAvmean at rest and during exercise; however exercise capacity did not diminish this age effect.

Dynamic spatio-temporal imaging of early reflow in a neonatal rat stroke model.

The aim of the study was to better understand blood-flow changes in large arteries and microvessels during the first 15 minutes of reflow in a P7 rat model of arterial occlusion. Blood-flow changes were monitored by using ultrasound imaging with sequential Doppler recordings in internal carotid arteries (ICAs) and basilar trunk. Relative cerebral blood flow (rCBF) changes were obtained by using laser speckle Doppler monitoring. Tissue perfusion was measured with [(14)C]-iodoantipyrine autoradiography. Cerebral energy metabolism was evaluated by mitochondrial oxygen consumption. Gradual increase in mean blood-flow velocities illustrated a gradual perfusion during early reflow in both ICAs. On ischemia, the middle cerebral artery (MCA) territory presented a residual perfusion, whereas the caudal territory remained normally perfused. On reflow, speckle images showed a caudorostral propagation of reperfusion through anastomotic connections, and a reduced perfusion in the MCA territory. Autoradiography highlighted the caudorostral gradient, and persistent perfusion in ventral and medial regions. These blood-flow changes were accompanied by mitochondrial respiration impairment in the ipsilateral cortex. Collectively, these data indicate the presence of a primary collateral pathway through the circle of Willis, providing an immediate diversion of blood flow toward ischemic regions, and secondary efficient cortical anastomoses in the immature rat brain.

Ovine middle cerebral artery characterization and quantification of ultrastructure and other features: changes with development.

Regulation of tone, blood pressure, and blood flow in the cerebral vasculature is of vital importance, particularly in the developing infant. We tested the hypothesis that, in addition to accretion of smooth muscle cells (SMCs) in cell layers with vessel thickening, significant changes in smooth muscle structure, as well as phenotype, extracellular matrix, and membrane proteins, in the media of cerebral arteries (CAs) during the course of late fetal development account for associated changes in contractility. Using transmission electron, confocal, wide-field epifluorescence, and light microscopy, we examined the structure and ultrastructure of CAs. Also, we utilized wire myography, Western immunoblotting, and real-time quantitative PCR to examine several other features of these arteries. We compared the main branch ovine middle CAs of 95- and 140-gestational day (GD) fetuses with those of adults (n = 5 for each experimental group). We observed a graded increase in phenylephrine- and KCl-induced contractile responses with development. Structurally, lumen diameter, media thickness, and media cross-sectional area increased dramatically from one age group to the next. With maturation, the cross-sectional profiles of CA SMCs changed from flattened bands in the 95-GD fetus to irregular ovoid-shaped fascicles in the 140-GD fetus and adult. We also observed a change in the type of collagen, specific integrin molecules, and several other parameters of SMC morphology with maturation. Ovine CAs at 95 GD appeared morphologically immature and poorly equipped to respond to major hemodynamic adjustments with maturation.

Middle cerebral artery median peak systolic velocity validation: effect of measurement technique.

We sought to validate center-specific published medians and estimate the effects of sonologist and Doppler measurement techniques on middle cerebral artery (MCA) peak systolic velocity (PSV) values. We studied 154 gravidas with normal singletons who underwent MCA PSV measurement at 18 to 35 weeks' gestation by one of three experienced sonologists. Pregnancies complicated by a known fetal anomaly (structural or aneuploidy), amniotic fluid volume disturbance, intrauterine growth restriction, multiple gestation, or isoimmunization were excluded. MCA PSV was measured using both manual caliper and auto-trace techniques. Regression models of log-transformed PSV values and gestational age were developed. Although auto-trace medians were significantly lower than those obtained with manual calipers ( P < 0.0001), they more closely approximated published medians used in clinical practice. Minimal intersonologist differences (maximum mean difference <3 cm/s) were statistically significant ( P < 0.01). Compared with manual caliper, auto-trace measurement yielded significantly lower medians. However, center-specific medians obtained by our sonologists using auto-trace more closely approximated published standards. Estimated interobserver variability suggested that different sonologists may utilize the same median values. We suggest that centers that utilize Doppler velocimetry for the prediction of fetal anemia examine their measurement protocol and consider formal confirmation of their own center-specific median values.

Intervalos de referência do pico de velocidade sistólica da artéria cerebral média fetal na população brasileira / Nomogram of fetal middle cerebral artery peak systolic velocity in a Brazilian population", "_i": "en

OBJETIVO: Determinar uma curva de referência baseada em múltiplos da mediana para o pico de velocidadesistólica da artéria cerebral média fetal. MATERIAIS E MÉTODOS: Realizou-se estudo de corte transversal com 143 gestantes normais entre 23 e 35 semanas. Realizou-se varredura bidimensional em corte axial docrânio fetal, incluindo os tálamos e o septo pelúcido, e em seguida acionou-se o modo color Doppler, visualizando-se a artéria cerebral média. O Doppler pulsátil foi disposto próximo à origem deste vaso, utilizando-se ângulo de insonação de menos de 20º. Para avaliar a correlação do pico de velocidade sistólica da artéria cerebral média com a idade gestacional, utilizou-se o coeficiente de correlação de Person (r). Por meio de modelos de regressão, construiu-se uma tabela de múltiplos da mediana para o pico de velocidade sistólica da artéria cerebral média em cada idade gestacional avaliada, e adicionalmente determinaram-se valores de referência para essa variável. RESULTADOS: Observou-se forte correlação entre o pico de velocidade sistólica da artéria cerebral média e a idade gestacional (r = 0,70; p = 0,001). Determinaram-se valores do pico de velocidade sistólica da artéria cerebral média para os seguintes múltiplos da mediana: 1,0; 1,29; 1,5;1,55. Determinaram-se os percentis 2,5 e 97,5 para o pico de velocidade sistólica da artéria cerebral média,variando de 24,33 cm²/s a 78,36 cm²/s. CONCLUSÃO: Um nomograma do pico de velocidade sistólica da artéria cerebral média fetal foi determinado.

OBJECTIVE: To determine a reference curve for the peak systolic velocity of fetal middle cerebral artery. MATERIALS AND METHODS: The authors developed a cross-sectional study with 143 healthy pregnant women between the 23rd and 35th gestational weeks. A bidimensional axial scan of the fetal skull wasperformed, including the thalami and pellucid septum. Subsequently, the middle cerebral artery was visualizedwith the color Doppler mode. The pulsed-wave Doppler transducer was positioned over the origin of this vessel, at < 20º insonation angle. The correlation between the peak systolic velocity of the middle cerebral artery and gestational age was evaluated by means of the Pearson's correlation coefficient (r). Regression models were utilized in the construction of a table with multiples of the medians of the middle cerebral artery peak systolic velocity for each gestational age. Additionally, reference values for this variable were determined. RESULTS: A strong correlation was observed between the middle cerebral artery peak systolic velocity and gestational age (r = 0.70; p < 0.001). Values of middle cerebral artery peak systolic velocity were calculated for the following multiples of the medians: 1.0, 1.29, 1.5, 1.55. The 2.5th and 97.5th percentiles were determined for the middle cerebral artery peak systolic velocity ranging between 24.33 cm²/s and 78.36 cm²/s. CONCLUSION: A nomogram for the fetal middle cerebral artery peak systolic velocity during the second half of pregnancy was generated.

Development affects in vitro vascular tone and calcium sensitivity in ovine cerebral arteries.

We have shown recently that development from neonatal to adult life affects cerebrovascular tone of mouse cerebral arteries through endothelium-derived vasodilatory mechanisms. The current study tested the hypothesis that development from fetal to adult life affects cerebral artery vascular smooth muscle (VSM) [Ca(2+)](i) sensitivity and tone through a mechanism partially dependent upon endothelium-dependent signalling. In pressurized resistance sized cerebral arteries ( approximately 150 microm) from preterm (95 +/- 2 days gestation (95 d)) and near-term (140 +/- 2 days gestation (140 d)) fetuses, and non-pregnant adults, we measured vascular diameter (microm) and [Ca(2+)](i) (nm) as a function of intravascular pressure. We repeated these studies in the presence of inhibition of nitric oxide synthase (NOS; with l-NAME), cyclo-oxygenase (COX; with indomethacin) and endothelium removal (E-). Cerebrovasculature tone (E+) was greater in arteries from 95 d fetuses and adults compared to 140 d sheep. Ca(2+) sensitivity was similar in 95 d fetuses and adults, but much lower in 140 d fetuses. Removal of endothelium resulted in a reduction in lumen diameter as a function of pressure (greater tone) in all treatment groups. [Ca(2+)](i) sensitivity differences among groups were magnified after E-. NOS inhibition decreased diameter as a function of pressure in each age group, with a significant increase in [Ca(2+)](i) to pressure ratio only in the 140 d fetuses. Indomethacin increased tone and increased [Ca(2+)](i) in the 140 d fetuses, but not the other age groups. Development from near-term to adulthood uncovered an interaction between NOS- and COX-sensitive substances that functioned to modulate artery diameter but not [Ca(2+)](i). This study suggests that development is associated with significant alterations in cerebral vascular smooth muscle (VSM), endothelium, NOS and COX responses to intravascular pressure. We speculate that these changes have important implications in the regulation of cerebral blood flow in the developing organism.

Cerebral artery sarcoplasmic reticulum Ca(2+) stores and contractility: changes with development.

To test the hypothesis that sarcoplasmic reticulum (SR) Ca(2+) stores play a key role in norepinephrine (NE)-induced contraction of fetal and adult cerebral arteries and that Ca(2+) stores change with development, we performed the following study. In main branch middle cerebral arteries (MCA) from near-term fetal ( approximately 140 days) and nonpregnant adult sheep, we measured NE-induced contraction and intracellular Ca(2+) concentration ([Ca(2+)](i)) in the absence and presence of different blockers. In adult MCA, after thapsigargin (10(-6) M), the NE-induced responses of tension and [Ca(2+)](i) were 37 +/- 5 and 47 +/- 7%, respectively, of control values (P < 0.01 for each). In the fetal artery, in contrast, this treatment resulted in no significant changes from control. When this was repeated in the absence of extracellular Ca(2+), adult MCA increases in tension and [Ca(2+)](i) were 32 +/- 5 and 13 +/- 3%, respectively, of control. Fetal cerebral arteries, however, showed essentially no response. Ryanodine (RYN, 3 x 10(-6) to 10(-5) M) resulted in increases in tension and [Ca(2+)](i) in both fetal and adult MCA similar to that seen with NE. For both adult and fetal MCA, the increased tension and [Ca(2+)](i) responses to RYN were essentially eliminated in the presence of zero extracellular Ca(2+). These findings provide evidence that in fetal MCA, in contrast to those in the adult, SR Ca(2+) stores are of less importance in NE-induced contraction, with such contraction being almost wholly dependent on Ca(2+) flux via plasma membrane L-type Ca(2+) channels. In addition, they suggest that in both adult and fetal MCA, the RYN receptor is coupled to the plasma membrane Ca(2+)-activated K(+) channel and/or L-type Ca(2+) channel.