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At least 91 records · Page 5Linked to original sources
PubMed2000

True-lumen collapse in aortic dissection: part II. Evaluation of treatment methods in phantoms with pulsatile flow.

PURPOSE: To discover and evaluate the effective treatment methods to prevent or relieve true-lumen collapse in models of aortic dissection. MATERIALS AND METHODS: Two phantoms were built to simulate type B aortic dissection. After true-lumen collapse was induced, experiments were conducted to evaluate the effectiveness of clinically relevant variables in relieving the collapse. Variables included entry-tear size, branch-vessel flow distribution, distal reentry communication between the true and false limbs, aortic fenestrations, and pump output. To test the effect of closing the entry tear, a stent-graft was deployed over the entry tear under physiologic conditions in a mock-flow loop. The difference in the effect of each variable on the prevention and relief of true-lumen collapse was also investigated. RESULTS: It was more difficult to relieve true-lumen collapse than it was to prevent it. Placement of a stent-graft over the entry tear was the most effective method of relieving true-lumen collapse. Less-effective procedures included opening a false-lumen outflow branch and opening the distal reentry branch. Opening the fenestration-branch loops, meant to simulate the creation of artificial fenestrations in the intimal flap, did not relieve true-lumen collapse. CONCLUSION: The definitive treatment for true-lumen collapse in aortic dissection is direct repair of the entry tear to decrease false-lumen inflow. Otherwise, increasing the false-lumen outflow and/or creating distal fenestrations between the true and false lumina distal to the level of the compromised aortic branch are less-effective alternatives.

Aortic Dissection↗
PubMed1988

Superoxide dismutase and cytochrome oxidase in collapsed lungs: possible role in reexpansion edema.

This study examined the effects of lung collapse, a condition that causes relative hypoxia in lung tissues, on superoxide dismutase (SOD), cytochrome oxidase (cyt ox), and pyruvate kinase (py ki) activities in rabbits. Cyanide-insensitive respiration measurements were done in collapsed and contralateral lungs, as an index of intracellular free radical production. Rabbits' right lungs were collapsed for 7 days after which the animals were killed. We found that control rabbit lungs contained approximately 25 SOD units/mg DNA measured with 10(-5) M KCN (total SOD) and approximately 11 SOD units/mg DNA measured with 10(-3) M KCN (mitochondrial or MnSOD). Right lung collapse caused a 25% decrease in mitochondrial SOD activity after 7 days (P less than 0.05), whereas no significant changes occurred in right or left lungs' total SOD activity. In control rabbits cyt ox activity averaged approximately 0.009 mumol ferrocytochrome c.min-1.mg DNA-1. Right lung collapse caused a greater than 40% decrease in cyt ox activity after 7 days of collapse (P less than 0.05), whereas cyt ox activity in contralateral left lungs did not change. Pyruvate kinase activity, a marker for anaerobic glycolysis resulting from tissue hypoxia, increased 49% in collapsed right lungs (P less than 0.01). Cyanide-insensitive respiration was 83% higher in 7 day-collapsed lungs (2.28 +/- 0.66 microliters O2.min-1.g-1) compared with contralateral lungs (1.24 +/- 0.34, P less than 0.05), indicating increased O2-. and H2O2 production in this tissue after homogenization at normoxic PO2 (approximately 150 Torr).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2004

Prevention of early sudden circulatory collapse after the Norwood operation.

BACKGROUND: After modifications in our perioperative management protocol, we have observed a decrease in sudden circulatory collapse after the Norwood operation. The current study examines early outcomes after the Norwood operation in our unit in an attempt to identify variables that may have altered the risk of unexpected circulatory collapse. METHODS AND RESULTS: We studied 105 consecutive neonates who underwent a Norwood operation in our institution. Our treatment protocol has changed in the past 3 years to include the use of alpha-blockade with phenoxybenzamine (POB) for systemic afterload reduction and selective cerebral perfusion. Forty-eight infants had selective cerebral perfusion. Forty-two infants received POB. Sixty patients had hypoplastic left heart syndrome. There was no difference in age, diagnosis, number of neonates with weight <2.5 kg, aortic size diameter <2 mm, highest preoperative lactate level, and shunt size indexed to body weight among patients with or without use of POB. Twenty-five infants had circulatory collapse during the first 72 hours. Twelve of them could be explained by technical issues. Thirteen others who appeared clinically stable had early sudden circulatory collapse without an apparent cause. Sixteen out of 25 neonates died. Of those with technical problems, 8 out of 12 died. Based on the hazard function, 3 incremental risk factors for early circulatory collapse were technical issue at operation (P<0.001), longer cross-clamp time (P<0.007), and no use of POB (P<0.002). For a technically successful operation, freedom from circulatory collapse at 72 hours is 95% with the use of POB versus 69% without (P<0.002). Diagnosis, aortic size, atrioventricular valve function, birth weight, age at operation, and total circulatory arrest time and were not predictive of early sudden circulatory collapse. CONCLUSIONS: Recent changes in our treatment protocol have resulted in a decrease incidence of sudden circulatory collapse after the Norwood operation. Optimal surgical technique is the most important predictor of early survival. The use of aggressive afterload reduction with POB reduced the risk of early sudden arrest.

Adrenergic alpha-Antagonists↗
PubMed1990

Localization of upper airway collapse during sleep in patients with obstructive sleep apnea.

The present study was conducted to determine the effects of body position and sleep state, as well as the effect of uvulopalatopharyngoplasty (UPPP) on the regions over which the upper airway (UA) collapses during sleep. To accomplish this goal, 18 male patients with obstructive sleep apnea (OSA) underwent overnight polysomnography with simultaneous monitoring of pressures in the posterior nasopharynx, oropharynx, hypopharynx, and esophagus. From the profile of pressures recorded in the UA and esophagus, the regions over which the UA collapses during apneas could be determined. The patients were 54 +/- 14 y of age and were grossly obese with a body mass index of 37 +/- 2 kg/m2. They had moderately severe OSA with a mean apnea plus hypopnea index of 62 +/- 8 per hour. During NREM sleep, 10 of the 18 (56%) patients had collapse confined to the velopharyngeal or retropalatal segment of the upper airway. The remaining 44% of the patients demonstrated collapse of the retroglossal segment of the oropharynx located caudal to the inferior margin of the soft palate. Upper airway collapse at the level of the hyoid bone was not observed during NREM sleep. Observations made during REM sleep in nine patients demonstrated that collapse occurred in a more caudal segment of the UA in seven patients during REM than during NREM sleep. The effect of sleep position was evaluated in 10 patients and found to have little affect on the extent over which the UA collapsed during sleep independent of sleep state. The effects of UPPP on regional UA collapse were evaluated in a small group of six patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMedDate not supplied

High-resolution studies of lung surfactant collapse.

Survanta is a replacement lung surfactant (LS) used in the treatment of respiratory distress syndrome (RDS), the fourth leading cause of infant mortality in the United States. It consists of purified LS from bovine sources and retains the surfactant proteins (SP) SP-B and SP-C, both thought to be important in proper respiratory function. As such, it provides a useful and biologically relevant model system to probe the structure and function of natural LS. Here, we report results from high-resolution studies on model monolayers formed from Survanta to probe the mechanism of collapse at high surface pressure. Our results show the formation of two different collapse structures. At 62 mN/m, slightly below the collapse pressure, monolayer collapse occurs through buckling. Confocal fluorescence measurements on supported films reveal regions of overlapping phase structure in the films that mark the transition from monolayer to multilayer. Simultaneous near-field scanning optical microscopy fluorescence and force measurements show that the transition seen in the fluorescence measurements accompanies corresponding approximately 4-5 nm changes in membrane topography. This change in height is consistent with bilayer formation on monolayer collapse. Analysis of the phase structure near the transitions also suggests that the buckling occurs from a continuous film. However, when the film is compressed to its collapse pressure of 65 mN/m, buckling is no longer evident in the collapsed region. In addition, multilayers and lipid-protein aggregates that are up to 40 nm higher than the monolayer are observed in the collapsed film at this pressure.

Animals↗
PubMed2006

Prediction of collapse in femoral head osteonecrosis: a modified Kerboul method with use of magnetic resonance images.

BACKGROUND: The hypothesis that the combined necrotic angle measurement from magnetic resonance imaging scans predicts the subsequent risk of collapse in hips with femoral head necrosis was tested. METHODS: Thirty-seven hips with early stage osteonecrosis in thirty-three consecutive patients were investigated. With use of the modified method of Kerboul et al., we measured the arc of the femoral surface involved by necrosis on a midcoronal as well as a midsagittal magnetic resonance image (rather than an anteroposterior and a lateral radiograph) and then calculated the sum of the angles. On the basis of the magnitude of the resulting combined angle, hips were classified into four categories: grade 1 (<200 degrees), grade 2 (200 degrees to 249 degrees), grade 3 (250 degrees to 299 degrees), and grade 4 (>/=300 degrees). After the initial evaluations, the hips were randomly assigned to a core decompression group or a nonoperative group. Patients underwent regular follow-up until femoral head collapse or for a minimum of five years. RESULTS: Seven grade-4 hips and sixteen grade-3 hips had development of femoral head collapse by thirty-six months. Six of the nine grade-2 hips and none of the five grade-1 hips collapsed (log-rank test, p < 0.01). None of the four hips with a combined necrotic angle of </=190 degrees (the low-risk group) collapsed, all twenty-five hips with a combined necrotic angle of >/=240 degrees (the high-risk group) collapsed, and four (50%) of the eight hips with a combined necrotic angle between 190 degrees and 240 degrees (the moderate-risk group) collapsed during the study period. CONCLUSIONS: The Kerboul combined necrotic angle, as ascertained with use of magnetic resonance imaging scans instead of radiographs, is a good method to assess future collapse in hips with femoral head osteonecrosis. LEVEL OF EVIDENCE: Prognostic Level I. See Instructions to Authors on jbjs.org for a complete description of levels of evidence.

Adolescent↗
PubMed1991

[Vertebral collapse model: combined diagnostic imaging].

Ninety-eight consecutive patients with 344 collapsed vertebrae underwent conventional and/or digital radiography and MRI. Vertebral collapse was due to osteopenia (16 cases), trauma (17 cases), and vertebral osteonecrosis (3 cases). Other causes were: spondylodiscitis (9 patients), primary neoplasm (4 patients), metastases (37 patients), and hemomyelopathies (7 patients); 5 patients bore vertebral angiomas. Sixty-three patients also underwent CT and 25 bone scintigraphy. As far as collapsed vertebral endplates are concerned, according to a previous classification, outcomes were divided into 4 groups. Type 1 (focal concave collapse) was observed in 10% of benign lesions and in 1% of malignant ones; type 2 (diffuse concave collapse) in 24% of benign and in 16% of malignant lesions; type 3 (focal collapse with an acute angle) in 11% of benign and malignant lesions, and type 4 (diffuse collapse with an acute angle) in 11% of benign and in 26% of malignant lesions. Neural arch involvement was observed in 3% of benign lesions and in 16% of malignant ones; paravertebral soft-tissue involvement in 6% of benign and in 29% of malignant lesions; vertebral canal involvement in 11% of benign lesions and in 20% of malignant ones. The intervertebral disk proximal to vertebral collapse was more involved in benign lesions (24%) than in malignant ones (8%). MR signal followed 4 main patterns: low signal on T1-weighted images and high signal on proton-density and T2-weighted images (2% of benign lesions, 49% of malignant ones), low signal on all sequences (7% of benign lesions and 25% of malignant ones), isointense signal on all sequences (50% of benign and 21% of malignant lesions), and high signal on all sequences (41% of benign lesions and 0% of malignant ones).

Adolescent↗
PubMed1994

Clinical and biochemical characteristics of collapsed ultra-marathon runners.

To evaluate the characteristics of runners with exercise-associated collapse (EAC), we studied the time of onset of collapse, rectal temperatures, cardiovascular status, and incidence of readily identifiable medical conditions in 46 male athletes who collapsed during or after a 56-km ultramarathon footrace run on a cool day. Data were compared with 65 control runners who did not collapse in the same race. Weight changes during recovery were studied in a subsample of both groups. The majority (85%) of runners with EAC collapsed after they had completed the race; rectal temperatures (38.5 +/- 1.3 degrees C, mean +/- SD; range 35.5-42.0 degrees C) and supine heart rates (87.5 +/- 17.2 min-1; range 60-138) were only modestly elevated. Postrace serum sodium concentrations, changes in plasma volume, and mass during recovery were not significantly different from values in control runners. We conclude that: (i) most cases of EAC (85%) occur after the finish line; (ii) runners collapsing during the race are more likely to have a readily identifiable medical condition than runners collapsing after the finish line; (iii) runners collapse most frequently near cutoff times for medals and race closure times; and (iv) 16% of EAC casualties and 19% of control runners have identifable biochemical abnormalities.

Adult↗
PubMed2005

The effects of collapsing factors on F-actin content and microtubule distribution of Helisoma growth cones.

Growth cone collapsing factors induce growth cone collapse or repulsive growth cone turning by interacting with membrane receptors that induce alterations in the growth cone cytoskeleton. A common change induced by collapsing factors in the cytoskeleton of the peripheral domain, the thin lamellopodial area of growth cones, is a decline in the number of radially aligned F-actin bundles that form the core of filopodia. The present study examined whether ML-7, a myosin light chain kinase inhibitor, serotonin, a neurotransmitter and TPA, an activator of protein kinase C, which induce growth cone collapse of Helisoma growth cones, depolymerized or debundled F-actin. We report that these collapsing factors had different effects. ML-7 induced F-actin reorganization consistent with debundling whereas serotonin and TPA predominately depolymerized and possibly debundled F-actin. Additionally, these collapsing factors induced the formation of a dense actin-ring around the central domain, the thicker proximal area of growth cones [Zhou and Cohan, 2001: J. Cell Biol. 153:1071-1083]. The formation of the actin-ring occurred subsequent to the loss of actin bundles. The ML-7-induced actin-ring was found to inhibit microtubule extension into the P-domain. Thus, ML-7, serotonin, and TPA induce growth cone collapse associated with a decline in radially aligned F-actin bundles through at least two mechanisms involving debundling of actin filaments and/or actin depolymerization.

Actins↗
PubMed2004

Convergent and divergent signaling mechanisms of growth cone collapse by ephrinA5 and slit2.

EphrinA5 and slit2 are important repulsive guidance cues in the developing retinotectal system. Both ephrinA5 and slit2 cause growth cone collapse of embryonic chick retinal ganglion growth cones cultured on EHS laminin. However, the signaling mechanism that these guidance cues initiate to cause collapse remains unclear. Here we provide evidence that while both ephrinA5 and slit2 cause collapse in morphologically similar ways, the intracellular signaling leading to the collapse involves shared as well as divergent paths. Pharmacological inhibition of either phosphatidylinositol 3-kinase (PI3K) or src family kinases prevented both ephrinA5-mediated and slit2-mediated growth cone collapse. In contrast, the inhibition of nonclassical protein kinase C (PKC) isoforms blocked ephrinA5-mediated collapse, but did not interfere with slit2-mediated collapse. PI3K was copurified by affinity chromatography with either the ephrinA5 receptors (ephAs) or the slit2 receptor (roundabout). Colocalization studies have also shown that src family kinase members are recruited to the ephA and roundabout receptors upon activation. In contrast, PKC members are recruited to the ephA receptors, but not to the roundabout receptors, upon activation. This demonstrates distinct points of convergence and divergence between the two signaling molecules, ephrinA5 and slit2, and their repulsive guidance in the chick retinotectal system.

Analysis of Variance↗
PubMed2000

Two-state expansion and collapse of a polypeptide.

The initial phase of folding for many proteins is presumed to be the collapse of the polypeptide chain from expanded to compact, but still denatured, conformations. Theory and simulations suggest that this collapse may be a two-state transition, characterized by barrier-crossing kinetics, while the collapse of homopolymers is continuous and multi-phasic. We have used a laser temperature-jump with fluorescence spectroscopy to measure the complete time-course of the collapse of denatured cytochrome c with nanosecond time resolution. We find the process to be exponential in time and thermally activated, with an apparent activation energy approximately 9 k(B)T (after correction for solvent viscosity). These results indicate that polypeptide collapse is kinetically a two-state transition. Because of the observed free energy barrier, the time scale of polypeptide collapse is dramatically slower than is predicted by Langevin models for homopolymer collapse.

Animals↗
PubMed2003

Progressive collapse of transposed necrotic area after transtrochanteric rotational osteotomy for osteonecrosis of the femoral head induces osteoarthritic change. Mid-term results of transtrochanteric rotational osteotomy for osteonecrosis of the femoral head.

INTRODUCTION: Osteonecrosis of the femoral head is usually progressive, and once collapse of the femoral head develops, joint destruction almost invariably follows. Therefore, for partial osteonecrosis of the femoral head, various types of osteotomies have been developed in an attempt to save the femoral head and maintain the natural function of the hip joint. MATERIALS AND METHODS: We reviewed 25 hips in 21 patients for a mean follow-up period of 6.4 years after Sugioka's transtrochanteric anterior rotational osteotomy for osteonecrosis of the femoral head. RESULTS: The clinical results were excellent or good in 20 hips (80%), and radiological success was observed in 15 hips (60%) with an absence of both collapse of the newly established weight-bearing area of the femoral head and narrowing of the joint space. Progressive collapse of the transposed necrotic area was noted in 10 hips (40%), and of these 10 hips, narrowing of the joint space was observed in 7 (70%) at follow-up. A significant correlation was demonstrated between progressive collapse of the transposed necrotic area and narrowing of the joint space. Growth of an osteophyte of the femoral head was observed postoperatively in 16 hips (64%), particularly at anterior and lateral sites of the femoral head. CONCLUSIONS: Though collapse of a new weight-bearing area can be prevented, progressive collapse of the transposed necrotic area induces anterior joint instability, giving rise to osteoarthritic change. It is therefore concluded that prevention of the collapse of the transposed necrotic area is important for satisfactory long-term results.

Adult↗
PubMed2004

Sera from patients with collapsing focal segmental glomerulosclerosis increase albumin permeability of isolated glomeruli.

The collapsing variant of focal segment glomerulosclerosis (FSGS) is characterized by heavy proteinuria and rapid progression to renal failure. Its cause is not known. We have characterized a substance in the circulation of patients with classic FSGS that increases in vitro permeability of glomeruli to albumin (P(alb)) and causes proteinuria when injected into rats. Inclusion of normal serum prevents the increase in P(alb) caused by this FSGS factor. We investigated the effect of sera from patients with collapsing FSGS on P(alb), as well as the effect of inclusion of normal serum. Isolated glomeruli were incubated with serum from each of 11 patients with collapsing FSGS (1:50 dilution) or with patient serum and an equal volume of pooled normal serum. P(alb) was determined on the basis of changes in glomerular volume in response to an oncotic gradient. Sera from 10 of the 11 patients with collapsing FSGS increased P(alb) of isolated glomeruli to a value of 0.5 or greater. In each of the 5 cases tested, inclusion of normal serum abolished the increase in P(alb). Sera of patients with collapsing FSGS increased glomerular P(alb). Our finding that the increase in P(alb) is abolished by normal serum suggests that the substance and its mechanism of action are similar or identical to the FSGS factor we have isolated from the plasma of patients with recurrent FSGS. The presence of a circulating factor in collapsing FSGS has implications for prognosis and treatment in primary and recurrent collapsing FSGS.

Adolescent↗
PubMed2006

Inter-rater reliability for witnessed collapse and presence of bystander CPR.

OBJECTIVE: Witnessed collapse and bystander CPR are the variables most frequently associated with good outcome from out-of-hospital cardiac arrest (OOHCA). The reliability of abstracting witnessed collapse and bystander CPR from prehospital Emergency Medical Services (EMS) patient care records (PCRs) is not known. We sought to determine the inter-rater reliability for different methods of ascertaining and defining witnessed collapse and performance of bystander CPR. METHODS: A sample of 100 PCRs for patients with OOHCA was selected at random from a pool of 325 PCRs between May 2003 and January 2005. Paramedics used a drop down menu to indicate witnessed collapse and bystander CPR, and completed a narrative description of the event. An on-scene EMS physician also completed a data sheet. The PCR was examined by two separate evaluators to determine the presence of witnessed collapse and bystander CPR. A consensus was reached by three other reviewers using all available data sources. Inter-rater agreement was quantified using the unweighted kappa statistic. RESULTS: For witnessed collapse, there is substantial agreement between the following: individual evaluators (kappa=0.76, S.D.=0.07), individual evaluators and consensus group (kappa=0.61, S.D.=0.07 and 0.66, S.D.=0.07), and physician and consensus group (kappa=0.68, S.D.=0.08). Agreement between individual evaluators and the physician was fair to moderate (kappa=0.38, S.D.=0.07 and 0.44, S.D.=0.07). Agreement between individual evaluators, physician, consensus group and the PCR drop down menu was fair to moderate (kappa range 0.33, S.D.=0.09 to 0.54, S.D.=0.09). For bystander CPR, there is substantial agreement between the individual evaluators and the consensus group (kappa=0.64, S.D.=0.07 and 0.63, S.D.=0.06) and between the physician and the consensus group (kappa=0.61, S.D.=0.08). Agreement between the two individual evaluators is moderate (kappa=0.59, S.D.=0.07). Agreement between the physician and individual evaluators is fair (kappa=0.36, S.D.=0.07 and 0.38, S.D.=0.07). The PCR drop down menu had moderate to substantial agreement with the individual evaluators, physician, and consensus group (kappa range 0.50, S.D.=0.09 to 0.75, S.D.=0.09). CONCLUSIONS: Determination of witnessed collapse and bystander CPR during OOHCA may be less reliable than previously thought, and differences between methods of rating could influence study results.

Adult↗
PubMed2003

Near native structure in an RNA collapsed state.

Many large RNAs form conformationally collapsed, but non-native, states prior to folding to the native state or assembling with protein cofactors. Although RNA collapsed states play fundamental roles in RNA folding and ribonucleoprotein assembly processes, their structures have been poorly understood. We obtained 12 high-quality structural constraints for the collapsed state formed by the catalytic core of the bI5 intron RNA using site-specific cross-linking mediated by a short-lived reactant. RNA tertiary structures in the collapsed and native states are indistinguishable, even though only the native state forms a solvent-inaccessible core. Thus, structural neighbors in the collapsed state, including several long-range tertiary interactions, are approximately as close in space as in the native state, but RNA packing is sufficiently loose or dynamic to allow access by solvent. Binding by the obligate CBP2 protein cofactor has almost no effect on structural neighbors reported by cross-linking, even though protein binding chases the RNA from the collapsed state to the native state. Protein binding thus appears to promote only the final few angstroms of RNA folding rather than mediate global conformational rearrangements in the catalytic core. The bI5 RNA collapsed state functions to self-chaperone ribonucleoprotein assembly because this conformationally restrained structure lies very near that of the native state and excludes structures that otherwise misassemble efficiently.

Azides↗
PubMed2004

Memory effect in the chain-collapse process in a dilute polymer solution.

The effect of temperature perturbation on a single-chain-collapse process was studied for poly(methyl methacrylate) with the molecular weight M(w)=1.05 x 10(7) in the mixed solvent of tert-butyl alcohol+water (2.5 vol %). In the chain-collapse process after a quench from the theta; temperature to a temperature T(1), the temperature was changed from T(1) to T(2) at the time t(1) after the quench and returned to T(1) at the time t(1)+t(2). In the three stages at T(1), T(2), and T(1), measurements of the mean-square radius of gyration of polymer chains were carried out by static light scattering and the chain-collapse process was represented by the expansion factor as a function of time. An effect of chain aggregation on the measurements was negligibly small because of the very slow phase separation. For the negative temperature perturbation (T(1)>T(2)), the chain-collapse processes observed in the first and third stages were connected smoothly and agreed with the collapse process due to a single-stage quench to T(1). A memory of the chain collapse in the first stage at T(1) was found to persist into the third stage at the same temperature T(1) without being affected by the temperature perturbation of T(2) during t(2). The memory effect was observed irrespective of the time period of t(2). The positive temperature perturbation (T(1)<T(2)) showed an acceleration of the chain-collapse process.

Journal Article↗
PubMed2000

Phosphorylation of collapsin response mediator protein-2 by Rho-kinase. Evidence for two separate signaling pathways for growth cone collapse.

We previously identified Rho-associated protein kinase (Rho-kinase) as a specific effector of Rho. In this study, we identified collapsin response mediator protein-2 (CRMP-2), as a novel Rho-kinase substrate in the brain. CRMP-2 is a neuronal protein whose expression is up-regulated during development. Rho-kinase phosphorylated CRMP-2 at Thr-555 in vitro. We produced an antibody that specifically recognizes CRMP-2 phosphorylated at Thr-555. Using this antibody, we found that Rho-kinase phosphorylated CRMP-2 downstream of Rho in COS7 cells. Phosphorylation of CRMP-2 was observed in chick dorsal root ganglion neurons during lysophosphatidic acid (LPA)-induced growth cone collapse, whereas the phosphorylation was not detected during semaphorin-3A-induced growth cone collapse. Both LPA-induced CRMP-2 phosphorylation and LPA-induced growth cone collapse were inhibited by Rho-kinase inhibitor HA1077 or Y-32885. LPA-induced growth cone collapse was also blocked by a dominant negative form of Rho-kinase. On the other hand, semaphorin-3A-induced growth cone collapse was not inhibited by a dominant negative form of Rho-kinase. Furthermore, overexpression of a mutant CRMP-2 in which Thr-555 was replaced by Ala significantly inhibited LPA-induced growth cone collapse. These results demonstrate the existence of Rho-kinase-dependent and -independent pathways for growth cone collapse and suggest that CRMP-2 phosphorylation by Rho-kinase is involved in the former pathway.

Amino Acid Sequence↗
PubMed2003

Microtubule depolymerization rapidly collapses capillary tube networks in vitro and angiogenic vessels in vivo through the small GTPase Rho.

Maintenance of endothelial cell tube integrity is dependent on an intact cytoskeleton. We present data indicating that rapid collapse of endothelial tubular networks in vitro occurs in a dose-dependent manner after administration of microtubule-depolymerizing reagents but not after actin depolymerization. Pretreatment of endothelial cell networks with C3 exoenzyme or recombinant adenoviruses expressing dominant negative RhoA resulted in complete blockade of tube collapse, indicating a role for RhoA in these events. Microtubule depolymerization also resulted in activation of RhoA, whereas increased expression of constitutively active RhoA induced cell rounding and apoptosis of endothelial cells. Furthermore, following treatment with the chemotherapeutic agent vinblastine, rapid capillary tube network collapse occurred followed by endothelial cell apoptosis. Vinblastine, but not control agents, induced cleavage of procaspase-3, procaspase-9, and procaspase-8, along with the known caspase targets p21-activated kinase-2 and gelsolin, indicating that tube collapse caused a defined apoptotic response. Using a model of vascular endothelial growth factor-stimulated angiogenesis in vivo, vinblastine treatment also resulted in collapse and apoptosis of angiogenic blood vessels. Apoptotic endothelial cells stained strongly for cleaved caspase-3, and terminal dUTP nick-end labeling staining revealed fragmented nuclei in vinblastine-treated but not control angiogenic areas. Together, these findings indicate that microtubule-depolymerizing agents directly induce endothelial network collapse in vitro and in vivo leading to endothelial cell apoptosis in a manner dependent on the small GTPase, RhoA. In addition, these findings reveal a novel function for microtubule disrupting chemotherapeutic agents, namely their ability to rapidly collapse newly formed angiogenic vessels, which may contribute to their effectiveness in limiting angiogenesis and tumor growth.

Animals↗