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Biomedical subjects

B L Langille

Publications and source records attributed to B L Langille.

At least 37 records · Page 2Linked to original sources
PubMed1995

Cardiac malformation in neonatal mice lacking connexin43.

Gap junctions are made up of connexin proteins, which comprise a multigene family in mammals. Targeted mutagenesis of connexin43 (Cx43), one of the most prevalent connexin proteins, showed that its absence was compatible with survival of mouse embryos to term, even though mutant cell lines showed reduced dye coupling in vitro. However, mutant embryos died at birth, as a result of a failure in pulmonary gas exchange caused by a swelling and blockage of the right ventricular outflow tract from the heart. This finding suggests that Cx43 plays an essential role in heart development but that there is functional compensation among connexins in other parts of the developing fetus.

Animals↗
PubMed1995

Pressure wave propagation and input impedance in thoracic aorta of conscious newborn sheep.

Aortic hemodynamics were examined in eight conscious newborn sheep. Flow and pressure in the thoracic aorta and pressure in the distal abdominal aorta were measured under control conditions and during pressure changes caused by bottle feeding or during intravenous infusions of nitroprusside, norepinephrine, or angiotensin II. Vasoconstriction affected aortic impedance, pressure wave amplification, and wave velocity similarly whether induced by feeding or by drugs. Central hemodynamics in the lamb were surprisingly similar to hemodynamics in the sheep fetus despite major changes in cardiovascular function at birth, largely because pressure-related increases in pulse wave velocity postpartum compensated for increased arterial lengths and increased heart rate. Wave reflection effects on pressure-flow relations were more prominent during vasoconstriction and less prominent during nitroprusside. Wave reflections in both lambs and fetal sheep return to the heart in early diastole; therefore, they do not add to ventricular afterload. Early diastolic return of reflected waves characterizes adults of many species, and demonstration of the phenomenon throughout the perinatal period reinforces arguments for its adaptive value.

Animals↗
PubMed1995

A wave transmission model of the umbilicoplacental circulation based on hemodynamic measurements in sheep.

Electrical analog models of the umbilical circulation were developed based on hemodynamic measurements in fetal sheep. The umbilical artery was represented by a transmission line and the placenta by a resistive load. Model predictions of input impedance and pressure and flow waveforms agreed with in vivo measurements under baseline conditions, following placental embolization, and during angiotensin II infusion. A unique positive impedance phase observed at the heart rate frequency under baseline conditions was best explained by the unusual viscoelastic properties of the umbilical arterial wall and small load reflections. Furthermore, a short, less vasoactive segment of the umbilical artery in the retroperitoneal space had a large impact on the input impedance of the umbilical circulation, which was particularly apparent when the artery was constricted during angiotensin II infusion. The model indicated that reflections arising near the approximate location where the first arterial branches leave the main umbilical artery have a measurable impact on impedance spectra when load reflections are low.

Animals↗
PubMed1995

Expression of ICAM-1 and VCAM-1 and monocyte adherence in arteries exposed to altered shear stress.

Local shear stresses generated by blood flow exert direct mechanical effects on adhesion of circulating leukocytes to vascular endothelium, but their effects on expression of endothelial-leukocyte adhesion molecules have not been determined. Shear stress in rabbit carotid arteries was increased by 170% or decreased by 73% in 5 days by surgical manipulations. En face immunofluorescence staining with the monoclonal antibody Rb1/9 revealed that vascular cell adhesion molecule-1 (VCAM-1) expression was greatly increased under low shear stress, but the distribution of staining was patchy. Thus, 71.4 +/- 7.8% of fields were VCAM-1 positive versus 2.4 +/- 0.47% of fields in control arteries. Frequently, large regions showed consistent but heterogeneous staining. Occasionally, small islands of cells were labeled intensely. Monocytes, detected by use of the monocyte-specific antibody HAM 56, adhered to endothelium under low shear stress; 64.5 +/- 8.2% of the monocytes colocalized with detectable VCAM-1, although many (83.2 +/- 2.8%) VCAM-1-positive regions were devoid of monocytes. VCAM-1 expression also increased significantly but to a lesser extent when shear stress was approximately doubled. Thus, 8.7 +/- 1.5% of fields were VCAM-1 positive under high shear versus 2.5 +/- 0.87% under normal shear stress. No monocytes were detected at high shear stress. At normal shear stresses, intercellular adhesion molecule-1 (ICAM-1), detected by use of the monoclonal antibody Rb2/3, was extensively distributed; thus, 53.5 +/- 5.5% of fields contained ICAM-1-positive cells. The junctional regions of the cells were heavily stained.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Apoptosis (programmed cell death) in arteries of the neonatal lamb.

We have examined whether cell death contributes to postnatal remodeling of arteries in lambs. First, abdominal aortic smooth muscle cell proliferation rates fell from 2.87 +/- 0.08% per day at 3 days of age to 1.75 +/- 0.15% per day at 21 days. These proliferation rates would yield a 50% increase in DNA content in the absence of cell death. No increase in DNA content was observed (P < .05 for predicted versus measured accumulation); therefore, significant cell death was inferred. The same analysis did not indicate high cell-death rates in the carotid, renal, or iliac arteries; however, cell death was detected in situ by end-labeling partially degraded DNA with terminal deoxynucleotidyl transferase or by nuclear labeling with propidium iodide, a fluorescent dye that permeates only nonviable cells. Nuclei were labeled in all arteries, although labeling was most frequent in the abdominal aorta, a vessel that regresses substantially after birth. Cell death was apoptotic because DNA extracted from arteries and end-labeled with [32P]dCTP produced a series of low molecular weight bands (DNA ladder) on an agarose gel, a hallmark of apoptosis. The ladder was strong for neonatal abdominal aorta but weak for other arteries. Only weak laddering was observed for fetal abdominal aortas in late gestation, confirming that high apoptosis rates in this vessel were initiated after birth. Intense DNA ladders and frequent in situ labeling indicated high rates of apoptosis in the postnatal intra-abdominal umbilical artery, another vessel that regresses after birth. We conclude that apoptosis contributes to postpartum arterial remodeling. This contribution is greatest in arteries that regress after birth.

Animals↗
PubMed1994

Three patterns of distribution characterize the organization of endothelial microfilaments at aortic flow dividers.

Since actin microfilaments are essential in the maintenance of endothelial integrity and in the repair of injured endothelium, we have carried out a detailed study of the distribution of microfilaments in the immediate vicinity of aortic branches. Branches are of major interest because there is a predilection for atherosclerotic lesions near branch ostia. We made an extensive, systematic examination of branches of the aorta and iliac arteries using in situ staining of perfusion-fixed arteries. Microfilaments were localized using rhodamine phalloidin. Three patterns of staining were observed. Some endothelial cells showed prominent central stress fibers. Others had few central stress fibers but prominent peripheral fibers. Still others showed an intermediate pattern with some central and some peripheral fibers present. At small branch sites, the lip of the divider was more blunt, and there were more cells with peripheral actin. At large branches, cells with peripheral actin were confined mainly to the lip, while there were many more cells with prominent central fibers. We also found that major differences can occur over very small distances, so adjacent cells may have strikingly different patterns of microfilament distribution. These patterns appear to reflect the geometry of the flow divider and local variations in hemodynamic shear stress. The differences in microfilament distribution may reflect differences in endothelial functions which are essential in maintaining endothelial integrity.

Actin Cytoskeleton↗
PubMed1994

Perinatal accumulation of arterial wall constituents: relation to hemodynamic changes at birth.

We compared arterial growth to hemodynamic changes in the perinatal period in lambs. Blood pressure did not change significantly from 120 days gestation to 3 days postpartum, when it was 45.4 +/- 1.9 mmHg; however, pressure rose to 64.8 +/- 2.5 mmHg at 21 days postpartum. Thoracic and abdominal aortic and iliac and carotid arterial blood flows fell > 50% after birth but returned to fetal levels except in the abdominal aorta by 21 days postpartum. Blood flows in mesenteric (BFm) and renal (BFr) arteries increased between 120 days gestation (BFr = 13.4 +/- 1.4; BFm = 41.8 +/- 3.5 ml/min) and 140 days gestation (BFr = 25.9 +/- 1.8; BFm = 189 +/- 18 ml/min) and between 3 and 21 days postpartum (to BFr = 71.1 +/- 14.3; BFm = 334 +/- 59 ml/min). Elastin accumulation accelerated at 140 days gestation in all arteries except the thoracic aorta, in which elastin accumulation was always rapid. Collagen but not DNA accumulation also accelerated in most arteries. Postpartum dexamethasone (0.1 mg/kg twice a day) did not affect abdominal aortic elastin by 10 days of age (23.9 +/- 2.7 vs. 26.4 +/- 4.1 mg for controls); however, dexamethasone upregulated tropoelastin mRNA in fetuses. We hypothesize that cortisol stimulates elastin accumulation in late gestation. Postnatal elastin but neither collagen nor DNA correlated with blood flow changes at birth (r = 0.855, P < 0.05). We infer that accumulation of elastin is sensitive to blood flow rates during perinatal development.

Animals↗
PubMed1993

Remodeling of developing and mature arteries: endothelium, smooth muscle, and matrix.

In recent years, it has become increasingly clear that vascular structures readily remodel in response to hemodynamic cues associated with changes in blood flows. These remodeling processes are invoked by a wealth of developmental, physiologic, and pathologic phenomena. Current work is providing novel clues concerning flow sensing by endothelial cells, the signal transduction pathways that translate flow detection into endothelial responses, and some of the signals that are transmitted to the effector cells, the vascular smooth muscle cells in the media. However, most of these mechanisms relate to acute responses to altered flow, and we remain ignorant of how important they are in eliciting tissue remodeling. Also, there is very little information on the processes that accomplish "remodeling" beyond evidence that modulation of new tissue synthesis occurs. There is a potential for imaginative experiments to provide fundamental information on the genesis of the vascular structure-function relations, which now clearly span much of the pre- and postnatal life.

Animals↗
PubMed1993

Nonadrenergic noncholinergic autonomic mediation of pressor response to feeding in lambs.

We examined factors mediating a 70% increase in arterial blood pressure that occurs during feeding in newborn lambs. We report that the increase in blood pressure during feeding was significantly reduced (to approximately 50%) and delayed in onset by combined alpha- and beta-adrenergic blockade. Plasma angiotensin and vasopressin levels did not increase significantly during feeding, nor was the pressor response to feeding attenuated while using captopril to block the production of angiotensin II. Adrenalectomy or muscarinic cholinergic blockade with atropine was also unsuccessful in attenuating the pressor response to feeding. We demonstrated that the component of the pressor response to feeding that was insensitive to alpha, beta, and muscarinic blockade was mediated by the autonomic nervous system because it was completely eliminated by ganglionic blockade with hexamethonium. Thus nonadrenergic noncholinergic autonomic mechanisms mediate approximately half the pressor response to feeding in lambs.

Adrenal Glands↗
PubMed1993

Evidence that turbulence is not the cause of poststenotic dilatation in rabbit carotid arteries.

The purpose of this study was to relate local blood flow conditions to the development of poststenotic dilatation (PSD) in the common carotid arteries of rabbits. We investigated the effects of the geometry of the stenoses on PSD formation to gain insight into the mechanisms of this phenomenon. With short stenoses, the maximum diameter of the PSD after 3 weeks increased from about 25% to 50% above the proximal diameter by increasing the severity of the stenoses from 50% to 60% diameter reduction. By contrast, increasing the length of the constricted region of 60% stenoses did not affect the PSD, and in all cases, the site of maximum dilatation occurred within 3 tube diameters from the stenoses. In vitro studies were conducted with the photochromic tracer technique. The most striking observation was that the transition to turbulence did not occur with a 55% short stenosis. By increasing the severity of this short stenosis to 70%, the transition to very localized turbulence was triggered approximately 6 to 8 tube diameters from the stenosis during the early deceleration phase of the flow cycle. The transition point moved farther downstream by increasing the length of this moderate stenosis. This study demonstrated that PSD can occur under turbulence-free conditions, and even when turbulence was generated, the site of the PSD was remote from that of the localized turbulence zone. The wall shear stress pattern was determined for the long 60% stenosis.(ABSTRACT TRUNCATED AT 250 WORDS)

Aneurysm↗
PubMed1993

Monocyte adhesion and changes in endothelial cell number, morphology, and F-actin distribution elicited by low shear stress in vivo.

Left common carotid arteries of New Zealand white rabbits were ligated rostral to origin of the thyroid artery to reduce flow in the carotid upstream of this branch, and the vessels were examined 5 days later. Estimates of mean shear stress in the upstream carotid artery indicated a decrease of 73% (from 12.1 +/- 1.6 dynes/cm2 to 3.26 +/- 0.58 dynes/cm2). The contralateral common carotid artery carried collateral flow and experienced a 170% increase in shear stress (from 11.3 +/- 1.6 dynes/cm2 to 30.5 +/- 4.6 dynes/cm2). There was an adaptive reduction in the diameter in the left common carotid artery (low shear) from 2.07 +/- 0.06 mm to 1.75 +/- 0.12 mm, but the diameter of the right carotid was unchanged. Fluorescence microscopy and scanning electron microscopy of endothelium exposed to low shear revealed attachment of leukocytes (5.02 +/- 1.59 cells/mm2, mean +/- SE) that were identified as monocytes using the monoclonal antibody HAM 56. Laser confocal microscopy demonstrated that they were migrating across the endothelial cell monolayer. Fluorescence microscopy and scanning electron microscopy of left common carotid artery (low shear) also revealed cell morphology suggestive of endothelial cell desquamation. Endothelial cell loss was confirmed by morphometric determination of cell number (1.29 +/- 0.13 x 10(4) cells/mm length in experimental animals versus 1.71 +/- 0.08 x 10(4) cells/mm length in sham-operated animals). This endothelial cell loss may be an adaptation to a narrowing of carotid arteries exposed to low shear, which reduces luminal surface area of the vessel. Staining of F-actin with rhodamine phalloidin showed that endothelial cells exposed to low shear were less elongated and had fewer stress fibers than normal cells. By contrast, increasing shear stress by two- to threefold caused an increase in the number of stress fibers and a reduction in peripheral actin staining. Distal carotid ligation provided a consistent and well-defined in vivo technique for manipulating shear stresses imposed on a large population of endothelial cells.

Actins↗
PubMed1992

Factors determining aortic and umbilical blood flow pulsatility in fetal sheep.

The link between the flow pulsatility index (P.I.) and vascular resistance was examined by infusing vasoactive agents or by progressive embolization of the peripheral vascular bed. Experiments were performed on fetal sheep near term, 3 days after implantation of a flow probe, catheter-tip pressure transducers, and fluid-filled catheters to monitor hemodynamics in the umbilical artery and the descending thoracic aorta. Increasing placental and hind limb resistance by embolization with microspheres caused a progressive increase in flow P.I. whereas altering resistance with vasoactive agents had variable results. Results showed that flow P.I. was sensitive to impedance to pulsatile flow and pressure pulsatility in addition to vascular resistance. We conclude it is hazardous to use the flow P.I. to detect changes in vascular resistance particularly when these changes are induced by physiological adjustments or vasoactive agents.

Animals↗
PubMed1992

Changes in blood flow distribution during the perinatal period in fetal sheep and lambs.

We have measured total blood flows and blood flows per 100 g tissue to major tissues at 120 and 140 days gestation in fetal sheep and at 3 and 21 days of age in lambs (gestation period = 144 +/- 2 days). Between 120 and 140 days gestation, flow per 100 g tissue increased by 74, 150, and 317% in the renal, intestinal, and hepatic arterial beds, but no further significant change in flow was observed at 3 or 21 days postpartum. Blood flows per 100 g to cerebral hemispheres and cerebellar tissues also increased dramatically during late gestation (142 and 121%, respectively), but declined sharply by 3 days postpartum (73 and 75%, respectively). Brain blood flows at 21 days postpartum remained substantially below late gestational levels. Adrenal blood flows per 100 g more than doubled during late gestation, fell by more than half at birth, and only partially recovered by 21 days of age. Blood flows to carcass tissues did not change in late gestation, fell at birth, then partially recovered. Pre- and post-natal increases in brain blood flows were almost entirely attributable to increased perfusion rather than tissue growth, whereas large perinatal increases in flow to the diaphragm paralleled tissue growth. Tissue growth and increased perfusion per 100 g contributed almost equally to increased blood flows to kidneys postnatally, and to adrenal glands and the gastrointestinal tract prenatally.

Animals↗
PubMed1992

Thoracic aortic pressure-flow relationships and vascular impedance in fetal sheep.

Upper descending thoracic aortic pressures recorded from near-term fetal sheep resembled those recorded in mature animals, but diastolic thoracic aortic flows were much greater than those reported for adults. Furthermore, the pressure wave was not amplified during transmission along the aorta, as it is in adults. Descending thoracic impedance fell with increasing frequency to approximately 25% of resistance to steady flow and then showed oscillations typical of systems in which pulse wave reflections are important. Angiotensin II and norepinephrine infusions enhanced impedance oscillations and caused changes in apparent phase velocity in the aorta that were consistent with increased wave reflections. Angiotensin also increased aortic characteristic impedance from 0.0152 +/- 0.0013 to 0.0230 +/- 0.0024 mmHg.min.ml-1. The effects of nitroprusside infusions indicated reduced wave reflection effects. Embolization of the placenta and hindlimbs with 50-microns microspheres was used to elevate vascular resistance in these beds. Embolization caused aortic flow to fall to zero by late diastole, and changes in impedance and apparent phase velocity suggested increased wave reflections from the periphery. Characteristic impedance was increased to 0.0209 +/- 0.0031 mmHg.min.ml-1.

Angiotensin II↗
PubMed1992

Structural changes and recovery of function after arterial injury.

Repair and remodeling processes initiated by arterial injury are thought to be critical in the pathogenesis of important vascular disorders. However, how these processes are related to specific types of injury is not well defined. Consequently, we compared arterial responses to several types of injury. Segments of rabbit carotid arteries were injured by intraluminal passage of an inflated embolectomy catheter, by hyperdistending the arteries with sterile saline, or by flushing them briefly with Triton X-100. Ballooning and Triton treatment removed the endothelium while imposing hyperdistending or nonhyperdistending injury on the vessel media. Hyperdistension with sterile saline caused medial injury but only transient and focal endothelial denudation. All modes of injury caused medial damage that was repaired within 2-7 days as assessed by vessel wall DNA content and synthesis and by capacity to contract. In addition, ballooned arteries recovered their capacity to exhibit diameter reductions induced by decreased blood flow once the endothelium had regenerated. The two injuries that caused endothelial denudation, ballooning and Triton treatment, resulted in equal intimal thickening after 6 weeks despite lower short- and long-term rates of cell replication after Triton-induced injury. Only ballooning resulted in chronic turnover of intimal smooth muscle cells after injury. No neointimal proliferation followed hyperdistension with saline despite significant medial injury. These latter findings suggest that even severe medial injury does not lead to intimal proliferation in the absence of endothelial denudation.

Animals↗
PubMed1992

Pulsatile pressure-flow relations and pulse-wave propagation in the umbilical circulation of fetal sheep.

The relations between pulsatile pressures and flows in the umbilico-placental circulation have been investigated using chronically instrumented fetal sheep. Under resting conditions, mean arterial pressure fell by 30 +/- 6%, from 44 +/- 2 to 31 +/- 2 mm Hg between the aortic termination and the arteries feeding the cotyledons, and pressure waves were substantially damped during propagation between the two recording sites. This high flow resistance and wave attenuation are attributed to the very thick walls and extreme length of the umbilical arteries. Unique relations between pulsatile components of pressure and flow, characterized as vascular impedance spectra, were also observed. At rest, impedance to pulsatile flow was only slightly below resistance to steady flow, and impedance phase was positive at low frequencies. Pulse-wave reflections had more modest effects in this bed than others. Thus, oscillations in impedance spectra and percent wave transmission with increasing frequency, which are widely accepted manifestations of wave reflections, were relatively small. Positive impedance phases at low frequencies indicated that novel mechanisms influence phase relations between pressure and flow. A significant vascular compliance residing in the peripheral vascular beds could account for this findings. The vasodilator nitroprusside enhanced wave-reflection effects, whereas the vasoconstrictor angiotensin II reduced these effects. These changes were opposite to the effects of vasoactive substances in other systems, probably because these drugs act predominantly on the supply (umbilical) arteries rather than on the peripheral placental vasculature. When peripheral vascular resistance was selectively elevated by infusing 50-microns microspheres, reflection effects were enhanced: the pressure pulse in the umbilical artery was transmitted without attenuation, or was amplified, and impedance spectra more closely resembled patterns typical of other vascular beds. Specifically, impedance modulus fell sharply with increasing frequency, and impedance phase was negative at low frequency. In addition, we observed coordinated oscillations in impedance modulus and phase that are characteristic of beds that exhibit wave-reflection effects. These findings indicate that the specialized anatomy and control mechanisms observed in the umbilical circulation result in unique hemodynamic function, in which wave-propagation effects exert influences not readily predictable from studies on other systems.

Angiotensin II↗
PubMed1991

Arterial adaptations to altered blood flow.

Arterial remodeling in response to altered blood flow is believed to be critical to vascular adaptations to developmental, physiological, pathological, and therapeutically induced changes in blood flow. To assess this remodeling, we used left-to-right carotid anastomosis to increase blood flow in the right common carotid arteries of adult rabbits by 60%. After 2 months, these vessels exhibited no compensatory enlargement. In contrast, the same procedure performed in 5- to 6-week-old weanling rabbits resulted in accelerated growth of the vessels: diameters exceeded those of control arteries by 19% after 2 months. Common carotid arteries in adult rabbits remodeled to produce a diameter reduced by 23% when blood flow was reduced by 63% by external carotid ligation. This adaptation restored shear stress exerted on the vessel wall to control levels. The reduced diameter was not reversed when the vessels were maximally dilated with nitroprusside, adenosine, and forskolin; however, normal diameters were restored within 1 week when normal blood flows were reestablished. Thus, the adult arteries did not respond to increased blood flow produced by the anastomosis, but this procedure did reverse adaptations to decreased flow. In contrast, immature arteries were responsive to this increase in blood flow, even in the absence of prior flow modulation.

Adaptation, Physiological↗