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Biomedical subjects

V Lindner

Publications and source records attributed to V Lindner.

At least 73 records · Page 4Linked to original sources
PubMed1996

Egr-1-induced endothelial gene expression: a common theme in vascular injury.

A number of pathophysiologically relevant genes, including platelet-derived growth factor B-chain (PDGF-B), are induced in the vasculature after acute mechanical injury. In rat aorta, the activated expression of these genes was preceded by a marked increase in the amount of the early-growth-response gene product Egr-1 at the endothelial wound edge. Egr-1 interacts with a novel element in the proximal PDGF-B promoter, as well as with consensus elements in the promoters of other genes induced by endothelial injury. This interaction is crucial for injury-induced PDGF-B promoter-dependent expression. Sp1, whose binding site in the PDGF-B promoter overlaps that of Egr-1, occupies this element in unstimulated cells and is displaced by increasing amounts of Egr-1. These findings implicate Egr-1 in the up-regulated expression of PDGF-B and other potent mediators in mechanically injured arterial endothelial cells.

Animals↗
PubMed1996

[Forgotten pain].

A 55-year-old female patient developed a severe chronic lumbar pain syndrome over a period of 17 years. An intervertebral disc operation was performed 5 years after the start of the painful illness. The patient later developed resistance to therapy and was unable to stand or walk. She was confined to bed and wheelchair and socially completely withdrawn. Drug therapy and invasive therapeutic techniques escalated. An intrathecal catheter for morphine administration had to be removed owing to bacterial meningitis, and repeated malfunction led to several revisions of an epidural catheter. Withdrawal of the morphine therapy, carried out with the patient's agreement, was complicated by an epileptic seizure and an acute circulatory failure with cerebral hypoxia. The succeeding severe amnestic syndrome extinguished all recollection of the last 20 years, including the entire course of the painful illness. The patient could then be mobilised without pain. Consistent care avoided a relapse into the pain syndrome as the amnestic syndrome gradually receded. The patient was fully able to accept responsibility and not longer required special pain therapy. The course demonstrates that chronic pain disorders of a predominantly psychodynamic, and therefore corticocerebral, genesis are dependent on an intact memory. In such cases memory failure can induce pain relief.

English Abstract↗
PubMed1996

Expression of VEGF receptors in arteries after endothelial injury and lack of increased endothelial regrowth in response to VEGF.

Vascular endothelial growth factor (VEGF) is an endothelial cell-specific factor with angiogenic effects in vivo and mitogenic effects in vitro. Administration of VEGF has been reported to stimulate endothelial growth in denuded arteries and new blood vessel formation in models of induced tissue ischemia. In the present study, expression of VEGF and its receptors flk-l and flt-l was determined in injured aortas and carotid arteries of rats and mice. Neither VEGF nor flk-l mRNA was detectable in vascular cells. mRNA levels for flt-l were dramatically upregulated at the leading edge of a growing endothelial monolayer in vivo; however, these cells did not demonstrate increased replication after VEGF infusion. Furthermore, all doses and treatment protocols of VEGF failed to promote reendothelialization in denuded arteries. At sites of flt-l expression, VEGF increased permeability. These areas revealed a loss of endothelial contacts at the ultrastructural level. These findings suggest that VEGF is not a direct mitogen for large-vessel endothelium in vivo and that VEGF may play a role in abolishing contact inhibition, which may be a prerequisite for endothelial proliferation.

Animals↗
PubMed1996

Migration of arterial wall cells. Expression of plasminogen activators and inhibitors in injured rat arteries.

The expression of plasminogen activators and inhibitors was examined in denuded arteries. Within 5 days, smooth muscle cells (SMCs) on the luminal surface expressed the mRNA for tissue-type plasminogen activator (TPA), urokinase type plasminogen (UPA), the receptor for UPA (UPAR), and plasminogen activator inhibitor type-1 (PAI-1). Similar results were seen after 8 days. Six weeks later, only TPA mRNA was still expressed by SMCs on the luminal surface. En face casein zymograms revealed a net fibrinolytic activity in areas covered with luminal SMCs. Reverse zymography showed no antifibrinolytic activity in these zones. Quiescent endothelial cells did not express TPA, UPA, UPAR, or PAI-1 mRNA. Regenerating endothelium at the wound edge strongly expressed TPA. UPA, and UPAR, as well as PAI-1. UPA and UPAR expression was highly restricted to cells at the wound edge and was not present elsewhere. En face zymography showed no plasmin activity in endothelialized areas, and reverse zymography showed a net fibrinolytic activity in endothelialized zones. These results suggest that plasminogen activator and inhibitor expression correlates with the migration of both SMCs and endothelial cells into an arterial wound.

Animals↗
PubMed1996

Cloning and characterization of rat density-enhanced phosphatase-1, a protein tyrosine phosphatase expressed by vascular cells.

We have cloned from cultured vascular smooth muscle cells a protein tyrosine phosphatase, rat density-enhanced phosphatase-1 (rDEP-1), which is a probable rat homologue of DEP-1/HPTP eta. rDEP-1 is encoded by an 8.7-kb transcript and is expressed as a 180- to 220-kD protein. The rDEP-1 gene is located on human chromosome 11 (region p11.2) and on mouse chromosome 2 (region 2E). The cDNA sequence predicts a transmembrane protein consisting of a single phosphatase catalytic domain in the intracellular region, a single transmembrane domain, and eight fibronectin type III repeats in the extracellular region (GenBank accession number U40790). In situ hybridization analysis demonstrates that rDEP-1 is widely expressed in vivo but that expression is highest in cells that form epithelioid monolayers. In cultured cells with epitheliod morphology, including endothelial cells and newborn smooth muscle cells, but not in fibroblast-like cells, rDEP-1 transcript levels are dramatically upregulated as population density increases. In vivo, quiescent endothelial cells in normal arteries express relatively high levels of rDEP-1. During repair of vascular injury, expression of rDEP-1 is downregulated in migrating and proliferating endothelial cells. In vivo, rDEP-1 transcript levels are present in very high levels in megakaryocytes, and circulating plates have high levels of the rDEP-1 protein. In vitro, initiation of differentiation of the human megakaryoblastic cell line CHRF-288-11 with phorbol 12-myristate 13-acetate leads to a very strong upregulation of rDEP-1 transcripts. The deduced structure and the regulation of expression of rDEP-1 suggest that it may play a role in adhesion and/or signaling events involving cell-cell and cell-matrix contact.

Amino Acid Sequence↗
PubMed1996

Expression of NF-kappa B and I kappa B-alpha by aortic endothelium in an arterial injury model.

Endothelial cells at sites of inflammatory responses express a variety of genes that are under the control of nuclear factor NF-kappa B, a transcription factor that with its inhibitors may be linked in an autoregulatory system that can be activated by multiple signals relevant to vascular pathophysiology. A model of limited endothelial denudation in the aorta of rats and mice was used to study the role of NF-kappa B and the inhibitor I kappa B-alpha Using en face techniques for in situ hybridization and immunostaining, normal endothelium showed diffuse cytoplasmic immunoreactivity for the NF-kappa B components p50 and p65 as well as the inhibitor I kappa B-alpha Within 45 minutes after wounding, nuclear staining for both NF-kappa B components was noticeable in the endothelial cells at the wound edge, which was followed by a dramatic induction of VCAM-1 mRNA and protein 3 hours later. Leading edge endothelial cells also responded with up-regulated expression of both NF-kappa B components and I kappa B-alpha. The increased expression of p50, p65, VCAM-1, and I kappa B-alpha persisted in replicating endothelium that was associated with adhesion of monocyte/macrophages to these cells. Expression levels returned to normal after regeneration. Our data establish for the first time the presence of the NF-kappa B/I kappa B-alpha system in the vasculature and demonstrate a correlation between activation of the regulatory system and induction of a kappa B-dependent endothelial adhesion molecule in an animal model of arterial injury. This autoregulatory system may be an important homeostatic mechanism in the vessel wall.

Animals↗
PubMed1996

[18 months long-term analysis of effectiveness, safety and tolerance of sumatriptan s.c. in acute therapy of migraine attacks].

The aim of the open prospective study was to investigate the efficacy, safety and tolerability of subcutaneous sumatriptan in acute migraine treatment. Patient self-treatment was monitored over a time period of 6-18 months with 6 mg of sumatriptan administered subcutaneously by an autoinjector. In total, 2,263 patients participated in the study. Headache intensity was documented by the patient in a headache diary before and 1 and 2 h after application. During the study period from October 1991 to June 1993, 43,691 migraine attacks were investigated. Treatment with sumatriptan was efficient in 89.5% of the attacks. Headache relief was achieved in 71%. Headache reoccurred in 22.7% of the attacks, and therefore a second injection was administered. An intraindividual treatment efficacy of 80-100% was achieved in 82.9% of the patients. During long-term treatment the ratio of effective treatment and headache frequency was constant; 4.9% of the patients withdrew from the study because of adverse events and because they felt the treatment was not effective. A total of 44.5% of the patients reported adverse events that were serious in 1.7%. Subcutaneous self-treatment with sumatriptan in the acute treatment of migraine is effective and well tolerated by the patients.

Adult↗
PubMed1996

Albumin as a sealant for a polyester vascular prosthesis: its impact on the healing sequence in humans.

OBJECTIVE: Although the healing characteristics of albumin impregnated vascular prostheses have been extensively studied in animal models, they have never been studied in humans. We therefore examined the healing sequence and the albumin degradation rate of this type of prosthesis harvested from humans. We also addressed the possible relationship between the implantation of cross-linked albumin and a specific inflammatory reaction. METHODS: Thirty albumin-impregnated polyester vascular prostheses were collected in our institution from January 1991 to February 1993. The mean duration of implantation of the prostheses was 8.4+/-9.7 (SD) months (range: 1 hour to 26 months). Twenty two prostheses were patent at the time of explantation and 4 had been thrombosed for less than 24 hours. In 18 cases, the prostheses were surgically removed because of a complication or a reoperation, and during an autopsy in 12 cases. Each harvested specimen was submitted to histological and immunohistochemical studies in order to demonstrate the presence of human albumin sealant, and to determine the inflammatory cell constituents. RESULTS: The albumin-impregnated prostheses were poorly infiltrated by healing tissues after 2 years of implantation. An external capsule was constantly observed after 2 months of implantation with a nonspecific chronic inflammatory reaction localized between the capsule and the polyester yarns. We observed large amounts of albumin sealant after 2 months, a gradual degradation with time, and traces after 2 years of implantation in humans. The luminal surface of the explant was mainly covered with organized fibrin. No histological signs of a specific inflammatory reaction were observed. CONCLUSIONS: The healing of the albumin impregnated prosthesis was poor and the degradation rate of the albumin sealant was significantly delayed, when compared to animal models. This difference in degradation rate could be related to interspecies differences of phagocytic cells enzymatic machinery. Finally, implantation of glutaraldehyde cross-linked albumin in humans is safe, since we observed an aspecific chronic foreign body inflammatory reaction.

Aged↗
PubMed1995

Expression of platelet-derived growth factor ligands and receptors by rat aortic endothelium in vivo.

In situ hybridization and immunostaining were used to study the time course of expression for platelet-derived growth factor (PDGF) ligands and receptors in endothelium of the rat aorta after injury. The PDGF-A and -B chains were expressed in endothelial cells at the wound edge within 4 h after injury, but no expression was detectable in uninjured endothelium. PDGF alpha-receptor was expressed in a pattern similar to the PDGF-A chain, while expression of PDGF beta-receptor was not detected at any time. Expression of the PDGF-B chain remained elevated in endothelial cells at the leading edge even at later measurements when these cells had stopped replicating. Smooth muscle cells (SMCs), which are absent from the intima of the normal aorta and are known to express PDGF beta-receptors, were predominantly found to migrate into the intima near the endothelial leading edge where PDGF-B was expressed. These data suggest a paracrine role for endothelial PDGF in SMC migration.

Animals↗
PubMed1995

A subpopulation of smooth muscle cells in injured rat arteries expresses platelet-derived growth factor-B chain mRNA.

Proliferation of smooth muscle cells (SMCs) and formation of a neointima are characteristics of the response of rat carotid arteries to balloon injury. Rat platelet-derived growth factor (PDGF)-B was cloned, thus allowing us to use species-specific probes to carry out in situ hybridization on the surface of injured arteries. A distinct population of luminal SMCs (7% to 10%) in the developing neointima expressed PDGF-B mRNA, but very few luminal SMCs still expressed PDGF-B (0.5%) when the lesion had stopped growing. Primary SMC cultures revealed expression of PDGF-B mRNA in 1.6% of SMCs derived from normal tunica media and in 11% of SMCs derived from the neointima. These data demonstrate that SMCs in the injured vessel wall are heterogeneous with regard to PDGF-B expression and that subculturing of these cells may give rise to cultures that are either positive or negative for PDGF-B expression. Furthermore, with abundant expression of the PDGF receptor beta-subunit expressed by intimal SMCs, our findings provide evidence that PDGF-B synthesized by these cells may be involved in intimal lesion formation via a paracrine or autocrine mechanism.

Amino Acid Sequence↗
PubMed1995

Osteopontin and beta 3 integrin are coordinately expressed in regenerating endothelium in vivo and stimulate Arg-Gly-Asp-dependent endothelial migration in vitro.

Osteopontin is an Arg-Gly-Asp (RGD)-containing acidic glycoprotein postulated to mediate cellular adhesion and migration in a growing number of normal and pathological conditions through interaction with integrin molecules. In this report, we have investigated the potential contributions of osteopontin and one of its receptors, the alpha v beta 3 integrin, to endothelial regenerative processes by using both in vivo and in vitro models. In vivo, uninjured rat arterial endothelium had undetectable levels of osteopontin and beta 3-integrin mRNA by in situ hybridization. After balloon catheter denudation, osteopontin mRNA levels correlated temporally and spatially with active endothelial proliferation and migration, with the highest levels observed at the wound edge between 8 hours and 2 weeks after injury, declining to uninjured levels at 6 weeks, when regeneration was complete. Osteopontin protein levels, as determined by immunocytochemistry, paralleled the time course of mRNA expression. Likewise, beta 3-integrin mRNA and protein levels were substantially elevated in regenerating endothelial cells but were not detectable in uninjured or healed endothelium. In vitro, rat smooth muscle cell-derived and bacterial expressed mouse recombinant osteopontins both stimulated the adhesion and directed migration of bovine aortic endothelial cells through interactions with the alpha v beta 3 receptor. Structural mutants of osteopontin confirmed the importance of the RGD domain for both adhesion and migration of endothelial cells through alpha v beta 3. These data suggest important roles for osteopontin and beta 3 integrin in regenerating endothelium.

Animals↗
PubMed1995

Platelet-derived growth factor ligand and receptor expression by large vessel endothelium in vivo.

Using an injury model of the rat carotid artery and aorta, we have determined the time course of expression for PDGF ligands and receptors in endothelium by in situ hybridization and immunostaining. Platelet-derived growth factor (PDGF)-A and -B chains-were expressed in endothelial cells at the wound edge, but no expression was detectable in uninjured endothelium. PDGF-alpha receptor was expressed in a similar pattern as PDGF-A chain whereas expression of PDGF-beta receptor was not detected at any time. Expression of PDGF-B chain did not correlate with endothelial cell replication and a neutralizing antibody against PDGF-B had no effect on endothelial regrowth in the denuded aorta. Intimal smooth muscle cells are known to express PDGF-beta receptors and could thus be stimulated to migrate in response to PDGF-B from endothelial cells.

Animals↗
PubMed1995

Role of basic fibroblast growth factor and platelet-derived growth factor (B-chain) in neointima formation after arterial injury.

Balloon catheterization of rat arteries induces proliferation of smooth muscle cells (SMC) which leads to the formation of an intimal lesion. We have previously demonstrated that basic fibroblast growth factor (FGF-2) released from damaged SMC is responsible for initiating SMC proliferation, however, it is still unclear which factors are involved in the continued replication of intimal SMC. Over 95% of SMC accumulating in the intima within 8 days after balloon injury are replicating and were therefore studied as an example of a proliferating SMC, while intimal SMCs at 6 weeks after injury served as a model of quiescent SMC. When in situ hybridization for FGF-2 was carried out on en face preparations at various time points after balloon injury, increased expression of FGF-2 mRNA and protein were observed at early stages when SMC were replicating while no expression was detectable in quiescent SMCs. Strong immunoreactivity for FGF-2 was found in the cytoplasm and nucleus of proliferating SMC, whereas staining in quiescent SMC was predominantly nuclear. Platelet-derived growth factor B-chain (PDGF-B) was expressed by a subpopulation of luminal SMC during formation of the neointima. The time-course of expression for FGF-receptor 1 (FGFR-1) was similar to FGF-2 with an increase in proliferating SMC. Our data suggest that the FGF-2/FGFR-1 system may play a role in the continued proliferation of intimal SMCs, while PDGF-B may be promoting intimal lesion formation by stimulating SMC migration via its chemotactic effect.

Angioplasty, Balloon, Coronary↗
PubMed1994

[Amitriptyline in therapy of chronic tension headache].

In a double-blind, placebo-controlled trial, the effect of 75 mg of a slow-release formulation of amitriptyline on the clinical severity of chronic tension-type headache and on headache-associated neurophysiological parameters (EMG activity, exteroceptive suppression of temporal muscle activity, contingent negative variation (CNV) and experimental pain sensitivity) was investigated. All of the patients treated had a history of headaches of many years standing, and numerous failed attempts at treatment. In the amitriptyline group, a significant reduction in daily headache duration was already found in the third week of treatment, while in the placebo group no significant changes in headache duration were to be seen. In week 6 the amitriptyline group had a significantly shorter daily duration of headache than the placebo group. Treatment did not result in any significant effects on EMG recording of pericranial muscle activity either during relaxation or contraction, on exteroceptive suppression of the temporal muscle and on CNV. The sensitivity to suprathreshold experimental pain, however, was significantly reduced. The data show a statistically relevant reduction of daily headache duration in chronic tension-type headache. However, they also show that amitriptyline can only partly alleviate chronic headaches but cannot cure them.

Adolescent↗
PubMed1993

Small fibre function in primary autonomic failure.

A case of primary autonomic failure (AF) with uncomplicated Parkinson's disease is presented with clinical and neurophysiological data. Special emphasis is placed on new methods of examining impairment of unmyelinated sympathetic and afferent C-fibres. Sympathetic vasoconstrictor responses in the skin induced by deep inspiration were examined quantitatively with laser Doppler flowmetry. The vasoconstriction was markedly depressed in primary AF compared with healthy controls and similar to secondary forms of AF. Peripheral nociceptive C-fibre function was quantitatively assessed by measurement of axon reflex vasodilatation induced by histamine iontophoresis. The axon reflex vasodilatation was completely intact in primary AF in contrast to patients with secondary peripheral small fibre neuropathy. The results indicate that sympathetic C-fibres are considerably affected by the degenerative disease, whereas the afferent C-fibres seem to be totally preserved. Modern neurophysiological methods of testing sympathetic and afferent small fibre function in combination with other neurophysiological tests, e.g. brain-stem auditory evoked potentials, might help to diagnose and differentiate primary AF in early stages and make it easier to distinguish between secondary autonomic neuropathies of unknown origin that often also involve unmyelinated afferent fibres.

Afferent Pathways↗
PubMed1993

Expression of basic fibroblast growth factor and its receptor by smooth muscle cells and endothelium in injured rat arteries. An en face study.

Release of endogenous basic fibroblast growth factor (bFGF) has been shown to initiate smooth muscle cell (SMC) proliferation following balloon catheter denudation in rat arteries. The mechanisms that contribute to the continued replication of the cells that subsequently form the neointima are not well understood. We have examined expression of bFGF and fibroblast growth factor receptor 1 (FGFR-1) in luminal SMCs as well as endothelium at various times after injury, which allowed us to study both replicating as well as quiescent cells. Using in situ hybridization on en face preparations, we were able to detect mRNA in luminal cells that was not observed by analysis of artery cross sections. We demonstrate that mRNA for bFGF was found in replicating SMCs and endothelial cells. bFGF mRNA was not detectable in either cell type at quiescence despite nuclear staining for bFGF. Expression of FGFR-1 mRNA was observed in replicating endothelial and SMCs at similar times after injury. These data provide evidence that in injured arteries the ligand/receptor system of bFGF and FGFR-1 may be involved in the continued proliferative response of SMCs leading to neointima formation. Furthermore, our results suggest a role for bFGF in reestablishing the endothelial lining in denuded vessels.

Animals↗
PubMed1993

Mouse model of arterial injury.

In the present study, we established an injury model of the mouse carotid artery. Complete removal of the endothelium was achieved with a flexible wire. A platelet monolayer covered the denuded surface, and damage to underlying medial smooth muscle cells (SMCs) was detected. Injection of [3H]thymidine was used to determine the replication index for medial SMCs, which was found to be 1.6% at 2 days after denudation and 9.8% at 5 days. SMCs were observed in the intima by day 8 (replication index, 66%), and by 2 weeks the intimal lesion had a similar cell content as the media. In most animals, repair of the endothelial lining was complete 3 weeks after injury. The present model will allow us to use transgenic animals to address questions relevant to vascular biology and atherosclerosis.

Animals↗