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PubMed2004

[Cardio-MRT. The multimodal functional analysis of the future].

Since initial reports in the early 1990s cardiac magnetic resonance imaging (CMR) has matured and is likely to become an established method for routine cardiac diagnostics. The development of faster gradient-echo sequences and stronger magnetic fields has led to improved temporal and spatial resolution. Myocardial viability can be examined by morphological and functional analysis. Contrast enhanced MRI (ceMRI), perfusion measurements and regional wall motion analysis are the major diagnostic tools. The ability to image in arbitrary double oblique planes provides comprehensive visualization of the heart. The introduction of the MR navigator technique allowed for free-breathing motion corrected 3D coronary MR angiography with improved spatial resolution. Using this approach proximal and mid parts of the coronary arteries have been visualized. Subsequently, sensitivity and specificity for the detection of significant coronary stenoses has been evaluated in a multicenter trial demonstrating good sensitivity and specificity for the detection of significant left main and three vessel disease. However, specificity for the detection of single vessel disease was relatively low. Improved motion compensation techniques and novel imaging sequences (SSFP) are currently under investigation to further refine this technique. Despite these promising results coronary MR-angiography is not likely to replace conventional coronary angiography especially with regard to in-plane spatial resolution, coronary collateralization and in-stent restenosis. In contrast, coronary MR-angiography can provide useful morphological informations including functional analysis of the coronary vascular bed. The combination of a conventional cathlab with CMR may provide CMR-guided myocardial interventions. With further improvements in the catheter technology, CMR interventions using real-time imaging guidance will allow to take advantage of the excellent soft tissue contrast of CMR and the simultaneous visualization of the pulmonary, aortic and coronary vessels. CMR is advantageous for screening and follow-up examinations, and it offers comprehensive assessment of cardiac morphology and function in one single examination.

Cardiomyopathies↗
PubMed1999

Internal carotid artery patency following common carotid artery occlusion: management of the asymptomatic patient.

Rarely, internal carotid artery (ICA) patency is maintained above a common carotid artery occlusion (CCAO) through collateral flow of the ipsilateral external carotid artery or an aberrant ICA branch. Several small series report excellent results of ICA revascularization in relieving cerebral ischemic symptoms in these patients. The natural history of CCAO with patent ICA in the asymptomatic patient, however, is unknown. The Greenville Memorial Hospital Vascular Teaching Service registry and all carotid duplex scans done in the Greenville Hospital System vascular laboratory from January 1994 through December 1997 were reviewed. Data collection included chart review, phone interviews, and the review of angiograms and duplex scans. This study suggests that carotid duplex is more sensitive for detecting ICA flow after CCAO than routine contrast angiography. It also suggests that while rare in presentation, asymptomatic patients with CCAO and a patent ICA appear to have a benign neurologic course and can probably be observed without a high risk of stroke.

Carotid Artery, Common↗
PubMed1988

Significance of technetium-99m/thallium-201 overlap on simultaneous dual emission computed tomography in acute myocardial infarction.

To examine the significance of technetium-99m pyrophosphate/thallium-201 scintigraphic overlap as an indicator of identifying early coronary reperfusion (less than or equal to 3 hours), 32 patients, in whom coronary recanalization was attempted for acute myocardial infarction (AMI), underwent myocardial imaging 3 days after the onset of AMI. The imaging was performed by simultaneous dual emission computed tomography, which allows simultaneous recording of technetium-99m pyrophosphate and thallium-201 images and comparison between both images in the same slice. The patients were separated into 3 groups: 9 patients in whom reperfusion was successful and showed scintigraphic overlap (group A), 12 with successful recanalization but no overlap (group B) and 11 with neither coronary reflow nor overlap (group C). No patient in whom reperfusion failed showed scintigraphic overlap (p less than 0.05). Groups A and B were comparable in age, infarct vessel, collateral circulation, residual coronary stenosis and cumulative release of creatine kinase-MB isoenzyme. However, compared with group B, group A had a shorter interval between onset of AMi and reflow (2.5 +/- 0.8 vs 4.8 +/- 1.3 hours, p less than 0.001). The presence of scintigraphic overlap identified early coronary reflow with a sensitivity of 80%, specificity of 91%, positive predictive accuracy of 89% and negative predictive accuracy of 83%. Thus, technetium-99m/thallium-201 overlap on dual emission computed tomography can be used as an index of documenting early recanalization and might reflect the presence of salvaged myocardium adjacent to the necrotic tissue.

Clinical Enzyme Tests↗
PubMed1988

Direct demonstration of an N-methyl-D-aspartate receptor mediated component of excitatory synaptic transmission in area CA1 of the rat hippocampus.

The action of a new non-N-methyl-D-aspartate (NMDA) receptor antagonist, 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), on synaptic transmission in area CA1 of the rat hippocampus has been examined. Intracellular and extracellular recordings showed CNQX to be a potent antagonist of synaptic potentials evoked by stimulation of the Schaffer collateral-commissural fibre system. One to 2 microM CNQX was sufficient to reduce the excitatory postsynaptic potential (EPSP) by 50%. CNQX is therefore about 100 times more potent than previously available non-NMDA receptor antagonists. In the presence of CNQX, a small depolarizing potential could still be evoked. This potential was sensitive to the NMDA-receptor blocker, 2-amino-5-phosphonovaleric acid (APV), increased in size on depolarizing the neurone and also increased in size on removing Mg2+ from the perfusing medium. This residual EPSP therefore has characteristics which are consistent with its mediation via the NMDA receptor-coupled ionophore. These results indicate a dual composition of the monosynaptic excitatory potential in area CA1.

6-Cyano-7-nitroquinoxaline-2,3-dione↗
PubMed2003

Behavioural learning-induced increase in spontaneous GABAA-dependent synaptic activity in rat striatal cholinergic interneurons.

Cholinergic striatal interneurons play a crucial role in cognitive aspects of context-dependent motor behaviours. They are considered to correspond to the tonically active neurons (TANs) of the primate striatum, which phasically decrease their discharge at the presentation of reward-related sensory stimuli. The origin of this response is still poorly understood. Therefore, in the present paper, we have investigated whether synaptic changes establish in cholinergic interneurons from young rats that have learned a rewarded, externally cued sensorimotor task. Corticostriatal slices were prepared from both control and trained rats. No significant change in intrinsic membrane properties and evoked synaptic activity was observed in cholinergic interneurons, nor the responsiveness to exogenously applied dopaminergic and glutamatergic agonists was modified. Conversely, an increased occurrence of spontaneous bicuculline-sensitive depolarizing postsynaptic potentials (sDPSP) was recorded. The frequency of the GABAA-mediated sDPSP was increased in comparison to not-conditioned rats. Overall, these results suggest that after learning a rewarded sensorimotor paradigm an increased GABA influence develops on cholinergic interneurons. The origin of this effect might be searched in collaterals of GABAergic output spiny neurons as well as in GABAergic striatal interneurons impinging onto cholinergic interneurons. This intrastriatal mechanism might be involved in the phasic suppression of discharge of TANs at the presentation of reward-related sensory stimuli.

6-Cyano-7-nitroquinoxaline-2,3-dione↗
PubMed2004

Gene knockout of glycine transporter 1: characterization of the behavioral phenotype.

N-methyl-d-aspartate receptor (NMDAR) activation requires both the binding of glutamate to its recognition site and occupancy of the strychnine insensitive glycine modulatory site (GMS). Pharmacological studies suggest that the glycine transporter, GlyT1, maintains subsaturating concentrations of glycine at synaptic NMDARs. To characterize further the role of GlyT1, we generated mice in which the gene encoding GlyT1 was inactivated by homologous recombination through insertion of a PGK-Neo cassette in place of exons 2 and 3. Real-time quantitative PCR revealed no transcripts in newborn homozygous [GlyT1(-/-)] mice and a 50% reduction in heterozygous (HZ) [GlyT1(+/-)] mice as compared with WT littermates. The activity of Na(+)-dependent glycine transport in forebrain homogenates was similarly affected. Homozygous mice died within 12 h of birth. In acute hippocampal slices, exogenous glycine or d-serine (10 microM) enhanced NMDAR currents with Schaffer collateral stimulation in WT mice but not HZ mice, suggesting that the GMS was more occupied in the latter. The NMDAR/alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor ratio of the excitatory postsynaptic currents was significantly increased in the HZ mice. In the water maze, the HZ mice exhibited better spatial retention. Furthermore, HZ mice were less sensitive to an amphetamine disruption of prepulse inhibition than WT mice but were more sensitive to the effects of MK-801. Thus, reduced expression of GlyT1 enhances hippocampal NMDAR function and memory retention and protects against an amphetamine disruption of sensory gating, suggesting that drugs which inhibit GlyT1 might have both cognitive enhancing and antipsychotic effects.

Amino Acid Transport Systems, Neutral↗
PubMed2005

[Coronary angiography and clinical characteristics of ventricular septal rupture after acute myocardial infarction].

OBJECTIVE: To provide evidence for the prevention and treatment of ventricular septal rupture (VSR) after acute myocardial infarction (AMI) by analyzing clinical and coronary angiographical characteristics. METHODS: Data on clinical and angiographical characteristics, effects of medical and surgical treatment and survival rate in 46 patients with VSR were analyzed retrospectively using statistical SPSS 11.0 software. RESULTS: The incidence of VSR after AMI was 1.88%. The susceptible risk factors were advanced age, no reperfusion therapy, no previous angina/myocardial infarction, complicated with hypertension/hyperlipidemia, etc. The most common location of myocardial infarction was anterior wall together with inferior wall. Percentage of neutrophil, serum level of CRP and ESR increased in most cases. Pulmonary edema (by X-ray) occurred in 30 percent of the cases, and 50 percent of the cases had unstable hemodynamics (Killip III-IV). In cases with anterior wall related infarction, the location of rupture was usually at distal area of anteroseptal, and in cases with inferior wall together with posterior/right wall infarction, it was usually at basal posteroseptal. By coronary angiography, most of the patients were with single vessel or 3-vessel coronary disease, rarely with collateral circulation. Left anterior descending coronary was the most common criminal vessel, especially in its middle segment. In-hospital mortality was 65% by conservative therapy while it was 3.85% by surgical treatment. CONCLUSION: Early and successful revascularization is the key factor for the prevention of VSR after AMI. Echocardiography is a sensitive and simple method for diagnosis. Surgical treatment improves the survival rate significantly. Early surgery is feasible.

Aged↗
PubMed1999

Expression of early hippocampal CA1 LTP does not lead to changes in AMPA-EPSC kinetics or sensitivity to cyclothiazide.

We have analysed whether the expression of long-term potentiation (LTP) in rat hippocampal CA1 neurons involves a change in the kinetics of (S)-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor-mediated excitatory postsynaptic currents (EPSCs) (AMPA-EPSCs) or their susceptibility to the AMPA receptor modulator cyclothiazide. AMPA-EPSCs in the CA1 region were evoked by alternate stimulation of two independent Schaffer collateral-commissural inputs of slices of adult rat hippocampus. In the current-clamp mode a strong tetanus (100 Hz, 1 s) applied to one input (input I) induced stable LTP of AMPA-EPSCs in this input, while the control input (input II) remained unaffected. For neither input were EPSC rise time and decay kinetics significantly changed. The application of cyclothiazide prolonged the rise time and the decay time constants of the AMPA-EPSCs in both control and potentiated inputs to the same extent (Input I-rise time: 198+/-8%, decay: 148+/-12%; input II-rise time: 212+/-14%, decay: 144+/-19%; n=8). Furthermore, when present during tetanization cyclothiazide did not occlude LTP, suggesting that cyclothiazide and tetanic stimulation enhance AMPA-EPSCs via independent mechanisms. Our findings argue against changes in (de-)activation or desensitization of AMPA receptors as the molecular basis for the expression of LTP.

Animals↗
PubMed2004

[Primary prevention: physical activity].

Traditional risk factors such as smoking, hypertension and being overweight have received considerable attention in recent years, whereas physical activity as a preventive strategy does not enjoy the same public attention. In recent years the level of physical activity has decreased dramatically in children and adolescents in favor of time spent on the internet and in front of the TV. If this trend is allowed to develop along the same direction, a sharp increase in cardiovascular disease can be anticipated. The protective action of physical activity on the cardiovascular system has been well documented in large numbers of patients, and the basic physiological mechanisms have been elucidated. Metabolic changes comprise loss of weight, reduction in triglyceride and LDL levels, as well as an increase in HDL. Insulin sensitivity is enhanced in all tissues postponing the manifestation of diabetes mellitus. Shear forces created by physical activity induce ecNOS within the endothelial lining of the arteries. This enzyme is responsible for controlling vasomotion through the elaboration of NO which causes vasodilation in the smooth muscle within the vessel wall. Utilization of preformed collateral vessels has been postulated repeatedly; so far, however, it only could be documented in animals, not in humans. Nearly all studies concerned with primary prevention have shown a significant negative correlation between energy expenditure during exercise and cardiovascular mortality, even light and moderate exercise will result in a lower incidence. In order to eliminate a sedentary life style in children and adolescents, adequate programs should be initiated in all schools; they should aim for 60 min of physical activity on a daily basis.

Cholesterol, LDL↗
PubMed1987

Caffeine inhibits post-tetanic potentiation but does not alter long-term potentiation in the rat hippocampal slice.

The effects of caffeine were investigated on the extracellular excitatory postsynaptic potentials (EPSPs) recorded in the stratum radiatum of CA1 of the rat hippocampal slice in response to stimulation of the Schaffer collaterals. Caffeine in concentrations from 500 microM to 10 mM caused an increase in the amplitude of the EPSP, which reached a peak after 5-10 min perfusion. This increase was antagonized by pretreatment with 20 microM trifluoperazine. Paired-pulse facilitation, augmentation and potentiation were strongly inhibited by caffeine. Augmentation was most sensitive to caffeine, being abolished by 500 microM caffeine. Long-term potentiation (LTP) induced by high-frequency stimulation was not significantly inhibited by caffeine either by 5-10 min or by 60 min perfusion with 10 mM caffeine. Moreover, the caffeine-induced increase in the low-frequency EPSP could be reversed by 30 min washout, demonstrating that it was not an LTP type increase.

Afferent Pathways↗
PubMed1971

Neuronal pathway of the recurrent facilitation of motoneurones.

1. The recurrent facilitation of motoneurones is a disinhibition, i.e. a release of the motoneurones from a sustained hyperpolarization evoked by tonically active inhibitory interneurones. Only two groups of interneurones are known to receive recurrent inhibition from motor axon collaterals via Renshaw cells; the interneurones mediating the reciprocal Ia inhibition and the Renshaw cells themselves. The properties of these two groups of neurones were studied to determine if they could produce the tonic inhibition of motoneurones removed during recurrent facilitation.2. It was found that the tonic firing of Ia inhibitory interneurones is sensitive to anaesthetics to the same degree as is recurrent facilitation. The range of frequencies of tonic discharges of Renshaw cells appeared to be similarly low in unanaesthetized and anaesthetized preparations although in individual cells the discharge rates were decreased by anaesthesia.3. The recurrent inhibition of Ia interneurones inhibiting a given group of motoneurones and the recurrent facilitation of the same group of motoneurones were, as a rule, evoked from the same nerves, although in some cats the origin of the recurrent facilitation was somewhat wider. In contrast no evidence could be found that the Renshaw cells which inhibit a functional group of motoneurones are inhibited by volleys in the nerves from which recurrent facilitation is regularly evoked.4. It was concluded that the recurrent facilitation is caused mainly by inhibition of the tonic activity of Ia inhibitory interneurones and that it is thus a manifestation of the recurrent control of Ia reciprocal inhibition of motoneurones.

Action Potentials↗
PubMed2005

Reduced glycine transporter type 1 expression leads to major changes in glutamatergic neurotransmission of CA1 hippocampal neurones in mice.

To investigate the effects of persistent elevation of synaptic glycine at Schaffer collateral-CA1 synapses of the hippocampus, we studied the glutamatergic synaptic transmission in acute brain slices from mice with reduced expression of glycine transporter type 1 (GlyT1+/-) as compared to wild type (WT) littermates using whole-cell patch-clamp recordings of CA1 pyramidal cells. We observed faster decay kinetics, reduced ifenprodil sensitivity and increased zinc-induced antagonism in N-methyl-d-aspartate receptor (NMDAR) currents of GlyT1+/- mice. Moreover, the ratio alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor (AMPAR)/NMDAR was decreased in mutants compared to WT. Surprisingly, this change was associated with a reduction in the number of AMPARs expressed at the CA1 synapses in the mutants compared to WT. Overall, these findings highlight the importance of GlyT1 in regulating glutamatergic neurotransmission.

Action Potentials↗
PubMed1987

Routine clinical positron emission tomography for diagnostic cardiac imaging--a review.

Positron emission tomography, advanced through technical developments, has now evolved into a routinely applicable method for clinical investigation. The rubidium-82 generator, without the need for a cyclotron, provides a source of positron radionuclide which enables delineation of cardiac structures. Three characteristics of positron cameras are particularly essential for cardiac imaging: overlapping image planes to provide uniform sampling between detector rings, a high sensitivity to acquire high count rates, and clinically oriented software that is user-friendly. The most useful indications for positron emission tomography include assessment of myocardial perfusion (for which the diagnosis of coronary artery disease can be established with a sensitivity of 95 to 98% and specificity of 99 to 100%), assessment of the physiologic severity of coronary artery stenoses and the influence of interventions such as PTCA or thrombolysis, myocardial infarct imaging, assessment of viability of reversibly injured or ischemic cells, assessment of regional or global left ventricular function and analysis of collateral flow. The radiation burden to the patient is generally lower than that of standard cardiac nuclear tracer such as Tl-201. Thus, cardiac positron emission tomography provides information not previously available for better diagnosis and management of cardiac disease. This technique may obviate the need for other routinely-applied nuclear imaging techniques. Should the services of a cyclotron be available, the method offers, in addition, the possibility to perform complex studies of myocardial metabolism.

Coronary Circulation↗
PubMed1994

Development of specificity in corticospinal connections by axon collaterals branching selectively into appropriate spinal targets.

Corticospinal projections in adult rodents arise exclusively from layer V neurons in the sensorimotor cortex. These neurons are topographically organized in their connections to spinal cord targets. Previous studies in rodents have shown that the mature distribution pattern of corticospinal neurons develops during the first 2 weeks postnatal from an initial widespread pattern that includes the visual cortex to a distribution restricted to the sensorimotor cortex. To determine whether specificity in corticospinal connections also emerges from an initially diffuse set of projections, we have studied the outgrowth of corticospinal axons and the formation of terminal arbors in developing hamsters. The sensitive fluorescent tracer 1,1',dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate (DiI) was used to label corticospinal axons from the visual cortex or from small regions of the forelimb or hindlimb sensorimotor cortex in living animals at 4-17 days postnatal. Initially axon outgrowth was imprecise. Some visual cortical axons extended transiently beyond their permanent targets in the pontine nuclei, by growing through the pyramidal decussation and in some cases extending as far caudally as the lumbar enlargement. Forelimb sensorimotor axons also extended past their targets in the cervical enlargement, in many cases growing in the corticospinal tract to lumbar levels of the cord. By about 17 days postnatal these misdirected axons or axon segments were withdrawn from the tract. Despite these errors in axon trajectories within the corticospinal tract, terminal arbors branching into targets in the spinal gray matter were topographically appropriate from the earliest stages of innervation. Thus visual cortical axons never formed connections in the spinal cord, forelimb sensorimotor axons arborized only in the cervical enlargement, and hindlimb cortical axons terminated only in the lumbar cord at all stages of development examined. Corticospinal arbors formed from collaterals that extended at right angles from the shafts of primary axons, most likely by the process of interstitial branching after the primary growth cone had extended past the target. Once collaterals extended into the spinal gray matter, highly branched terminal arbors formed within 2-4 days, beginning at about 4 and 8 days postnatal for the cervical and lumbar enlargements, respectively. These results show that specificity in corticospinal connectivity is achieved by selective growth of axon collaterals into appropriate spinal targets from the beginning and not by the later remodeling of initially diffuse connections. In contrast, errors occur in the initial outgrowth of axons in the corticospinal tract, which are subsequently corrected.

Animals↗
PubMed1989

Efferent tectal cells of crucian carp: physiology and morphology.

Tectal cells of the crucian carp (Carassius ararssius) showing antidromic responses evoked by rhombencephalic electrical stimulation were physiologically studied and subsequently stained with Lucifer Yellow CH. The stained efferent tectal cells were fusiform, horizontal, and multipolar. The main axon of these efferent tectal cells descended along the wall of the deep tegmentum and could be traced to the motor area below the cerebellum. The axons gave off their collaterals in several brain areas: 1) descending collaterals in the torus semicircularis, dorso-lateral tegmental area and mesencephalic reticular formation and 2) an ascending collateral in the area between the hypothalamus and tegmentum. Fifty percent of the efferent cells were unresponsive to visual stimuli, but some of these cells were activated by visual or tactile stimulation in conjunction with rhombencephalic electrical stimulation. On the other hand, most of the visually active cells were On-transient and movement sensitive with habituation and some were bimodal.

Action Potentials↗
PubMed1996

NO-induced oxidative stress and glutathione metabolism in rodent and human cells.

Nitric oxide (NO.), a radical species produced by many types of cells, is known to play a critical role in both regulatory processes and cell defense, yet it may also participate in collateral reactions, leading to DNA damage and cell death in both NO-generating and neighboring cells. Glutathione has been shown to protect cells from the toxic effects of free radicals and reactive oxygen species. The goal of this study was to investigate whether differences in glutathione metabolism could account for the resistance or sensitivity to cell killing by NO.. The cytotoxic effect of NO. was examined in CHO-AA8 (Chinese Hamster Ovary) cells and TK6 (human lymphoblastoid) cells pretreated with L-buthionine SR-sulfoximine (BSO), a potent inhibitor of gamma-glutamylcysteine synthetase, and with 1,3-bis-(2-chloroethyl)-1-nitrosourea (BCNU), an irreversible inhibitor of glutathione reductase. The consequences resulting from the depletion of glutathione levels and from the arrest of oxidoreduction allowed us to show the involvement of glutathione in protecting cells from NO. and to investigate the importance of changes in glutathione metabolism on NO-induced toxicity. In CHO-AA8 cells, we found that treatment with NO. resulted in the oxidation of reduced glutathione (GSH) to oxidized glutathione (GSSG) and to mixed glutathione disulfides (GSSR). The resulting depletion of GSH stimulated its de novo synthesis, enabling the cells to resist killing by NO.. A slight difference in GSH metabolism was observed in TK6 cells. NO. led to an increase in GSSG levels similar to that observed in CHO-AA8 cells, however, a decrease in GSH levels, no change in GSSR levels, and higher levels of toxicity were also found, suggesting that NO-treated TK6 cells are not as competent in GSH homeostasis as CHO cells. We conclude that GSH is involved in protecting cells from killing by NO. and that both de novo synthesis of GSH and GSSG reduction are important in maintaining an adequate level of protection for the cells.

Animals↗
PubMed2005

Relation of platelet activation to coronary angiographic severity and collateralization.

We investigated whether platelet activation can be correlated with angiographic severity and the degree of collateralization in coronary artery disease (CAD), as well as endothelial damage/dysfunction. No studies have attempted to correlate platelet activation status, as measured by soluble plasma markers (soluble CD40 ligand, soluble P-selectin, soluble glycoprotein V), with the appearance of diseased coronary arteries. We found evidence of increased platelet activation in CAD, but a lack of correlation between the degree of platelet activation and the angiographic disease severity, which may reflect the presence of disease elsewhere or the presence of coronary atheroma not detected by angiography.

Aged↗
PubMed2004

p21Cip1 levels differentially regulate turnover of mature endothelial cells, endothelial progenitor cells, and in vivo neovascularization.

p21(Cip1) (p21) controls cell cycle progression and apoptosis in mature endothelial cells (ECs) and regulates size and cycling of the hematopoietic progenitor cell pool. Because circulating endothelial progenitor cells (EPCs) contribute to postnatal neovascularization in addition to mature ECs, we investigated the regulation of ECs and EPCs in p21-deficient mice. Mature aortic EC proliferation was increased in homozygous p21(-/-) and heterozygous p21(+/-) mice, in which p21 protein levels are reduced to one third of wild-type (WT). In contrast, apoptosis sensitivity was increased by 3.5-fold only in p21(-/-), but not in p21(+/-) mice. Consistently, in vivo apoptosis of ECs within areas of neovascularization was elevated in p21(-/-) but not in p21(+/-) mice. EPC numbers were elevated 2-fold in p21(-/-) mice compared with WT (P<0.001), and clonal expansion capacity of EPCs was increased from 25+/-4 (WT) to 57+/-8 colony-forming units in p21(-/-) mice (P<0.005). EPC numbers and expansion were likewise increased in p21(+/-) mice. As the integrative endpoint, in vivo neovascularization reflecting all p21-affected parameters was increased over WT only in p21(+/-) (P<0.001), but not in p21(-/-) mice. In conclusion, reduced p21 protein levels of mice lacking one p21 allele are associated with increased proliferation of ECs and EPCs, whereas survival of ECs to apoptotic stimuli in vitro and in vivo is not impaired. Under these conditions, neovascularization was increased. In contrast, complete p21 deficiency did not result in an increased neovascularization despite increased mature EC and EPC proliferation. This may be due to the sensitization of ECs against apoptosis.

Alleles↗